Author: "Lipton, Stuart A." / Database: OAIster - Searchworks@Jio Institute Digital Library Search Results

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66 results on '"Lipton, Stuart A."'

1. Single‐Cell Patch‐Clamp/Proteomics of Human Alzheimer's Disease iPSC‐Derived Excitatory Neurons Versus Isogenic Wild‐Type Controls Suggests Novel Causation and Therapeutic Targets

Author: Ghatak, Swagata, Ghatak, Swagata, Diedrich, Jolene K, Talantova, Maria, Bhadra, Nivedita, Scott, Henry, Sharma, Meetal, Albertolle, Matthew, Schork, Nicholas J, Yates, John R, Lipton, Stuart A, Ghatak, Swagata, Ghatak, Swagata, Diedrich, Jolene K, Talantova, Maria, Bhadra, Nivedita, Scott, Henry, Sharma, Meetal, Albertolle, Matthew, Schork, Nicholas J, Yates, John R, and Lipton, Stuart A
Abstract: Standard single-cell (sc) proteomics of disease states inferred from multicellular organs or organoids cannot currently be related to single-cell physiology. Here, a scPatch-Clamp/Proteomics platform is developed on single neurons generated from hiPSCs bearing an Alzheimer's disease (AD) genetic mutation and compares them to isogenic wild-type controls. This approach provides both current and voltage electrophysiological data plus detailed proteomics information on single-cells. With this new method, the authors are able to observe hyperelectrical activity in the AD hiPSC-neurons, similar to that observed in the human AD brain, and correlate it to ≈1400 proteins detected at the single neuron level. Using linear regression and mediation analyses to explore the relationship between the abundance of individual proteins and the neuron's mutational and electrophysiological status, this approach yields new information on therapeutic targets in excitatory neurons not attainable by traditional methods. This combined patch-proteomics technique creates a new proteogenetic-therapeutic strategy to correlate genotypic alterations to physiology with protein expression in single-cells.
Published: 2024

2. Apoptotic cell death in disease—Current understanding of the NCCD 2023

Author: Associazione Italiana per la Ricerca sul Cancro, Italian Institute for Genomic Medicine, Compagnia di San Paolo, Vitale, Ilio [0000-0002-5918-1841], Pietrocola, Federico [0000-0002-2930-234X], Guilbaud, Emma [0000-0001-5261-1944], Aaronson, Stuart A. [0000-0002-4643-0474], Dieter, Adam [0000-0002-5668-5032], Agostini, Massimiliano [0000-0003-3124-2072], Agostinis, Patrizia [0000-0003-1314-2115], Alnemri, Emad S. [0000-0002-7295-3383], Altucci, Lucia [0000-0002-7312-5387], Amelio, Ivano [0000-0002-9126-5391], Andrews, David W. [0000-0002-9266-7157], Aqeilan, Rami I. [0000-0002-6034-023X], Arama, Eli [0000-0001-5953-0629], Balachandran, Siddharth [0000-0003-2084-1803], Bano, Daniele [0000-0002-9617-5504], Bartek, Jiri [0000-0003-2013-7525], Bazan, Nicolas G. [0000-0002-9243-5444], Bernassola, Francesca [0000-0002-8883-8654], Bertrand, Mathieu J. M. [0000-0001-9000-0626], Bianchi, Marco Emilio [0000-0002-5329-6445], Blander, J. Magarian [0000-0001-9207-1700], Blandino, Giovanni [0000-0002-6970-2241], Blomgren, Klas [0000-0002-0476-7271], Bortner, Carl D. [0000-0002-5444-6628], Bove, Pierluigi [0000-0002-4788-2982], Boya, Patricia [0000-0003-3045-951X], Broz, Petr [0000-0002-2334-7790], Damgaard, Rune Busk [0000-0002-1709-6534], Calin, George A. [0000-0002-7427-0578], Campanella, Michelangelo [0000-0002-6948-4184], Candi, Eleonora [0000-0001-8332-4825], Carbone, Michele [0000-0001-8928-8474], Carmona-Gutierrez, Didac [0000-0001-7548-7771], Cecconi, Francesco [0000-0002-5614-4359], Chen, Guo‑Qiang [0000-0002-7226-1782], Cheng, Emily H. [0000-0002-3595-2648], Chipuk, Jerry E. [0000-0002-1337-842X], Cidlowski, John A. [0000-0003-1420-0516], Ciechanover, Aaron [0000-0001-9184-8944], Ciliberto, Gennaro [0000-0003-2851-8605], Conrad, Marcus [0000-0003-1140-5612], Czabotar, Peter E. [0000-0002-2594-496X], D’Angiolella, Vincenzo [0000-0001-8365-9094], Daugaard, Mads [0000-0001-8383-055X], Dawson, Valina L. [0000-0002-2915-3970], De Maria, Ruggero [0000-0003-2255-0583], Debatin, Klaus-Michael [0000-0002-8397-1886], Deberardinis, Ralph J. [0000-0002-2705-7432], Degterev, Alexei [0000-0002-8240-7132], Del Sal, Giannino [0000-0003-2185-6003], Deshmukh, Mohanish [0000-0002-2597-5862], Di Virgilio, Francesco [0000-0003-3566-1362], Diederich, Marc [0000-0003-0115-4725], Dixon, Scott J. [0000-0001-6230-8199], El-Deiry, Wafik S. [0000-0002-9577-8266], Elrod, John W. [0000-0003-3925-2224], Engeland, Kurt [0000-0003-3525-0440], Fimia, Gian María [0000-0003-4438-3325], Ganini, Carlo [0000-0002-5839-3965], García-Sáez, Ana J. [0000-0002-3894-5945], Garg, Abhishek D. [0000-0002-9976-9922], Garrido, Carmen [0000-0003-1368-1493], Gavathiotis, Evripidis [0000-0001-6319-8331], Ghosh, Sourav [0000-0001-5990-8708], Green, Douglas R. [0000-0002-7332-1417], Gronemeyer, Hinrich [0000-0001-9454-2449}, Häcker, Georg [0000-0003-1058-5746], Hajnóczky, György [0000-0003-3813-2570], Hardwick, J. Marie [0000-0002-4847-2045], Haupt, Ygal [0000-0001-5925-0096], He, Sudan [0000-0002-0846-1210], Heery, David M. [0000-0002-5035-2392], Hengartner, Michael O. [0000-0002-7584-596X], Hetz, Claudio [0000-0003-1120-7966], Hildeman, David A. [0000-0002-0421-8483], Ichijo, Hidenori [0000-0002-5005-6438], Jäättelä, Marja [0000-0001-5950-7111], Janic, Ana [0000-0002-4200-2560], Joseph, Bertrand [0000-0001-5655-9979], Jost, Philipp J. [0000-0003-2454-0362], Kanneganti, Thirumala-Devi [0000-0002-6395-6443], Karin, Michael [0000-0002-2758-6473], Kashkar, Hamid [0000-0003-2796-1429], Kaufmann, Thomas [0000-0001-9906-874X], Kelly, Gemma L. [0000-0002-6533-1201], Kepp, Oliver [0000-0002-6081-9558], Kimchi, Adi [0000-0002-8236-8989], Klionsky, Daniel J. [0000-0002-7828-8118], Kluck, Ruth [0000-0002-7101-1925], Krysko, Dmitri V. [0000-0002-9692-2047], Kulms, Dagmar [0000-0001-6874-0548], Kumar, Sharad [0000-0001-7126-9814], Lavandero, Sergio [0000-0003-4258-1483], Lavrik, Inna N. [0000-0002-9324-309X], Liccardi, Gianmaria [0000-0002-2662-1281], Linkermann, Andreas [0000-0001-6287-9725], Lipton, Stuart A. [0000-0002-3490-1259], Lockshin, Richard A. [0000-0002-4389-4898], López-Otín, Carlos [0000-0001-6964-1904], Luedde, Tom [0000-0002-6288-8821], MacFarlane, Marion [0000-0001-7886-1159], Madeo, Frank [0000-0002-5070-1329], Malorni, Walter [0000-0002-1223-7000], Manic, Gwenola [0000-0003-3759-8029], Marchi, Saverio [0000-0003-2708-1843], Marine, Jean-Christophe [0000-0003-2433-9837], Martin, Seamus J. [0000-0002-8539-3143], Martinou, Jean-Claude [0000-0002-9847-2051], Mastroberardino, Pier G. [0000-0003-2364-4258], Medema, Jan Paul [0000-0003-3045-2924], Mehlen, Patrick [0000-0003-1743-5417], Meier, Pascal [0000-0003-2760-6523], Melino, Gerry [0000-0001-9428-5972], Melino, Sonia [0000-0001-7694-5279], Miao, Edward A. [0000-0001-7295-3490], Moll, Ute M. [0000-0003-1908-7516], Muñoz-Pinedo, Cristina [0000-0002-9120-664X], Murphy, Daniel J. [0000-0002-5538-5468], Niklison-Chirou, Maria Victoria [0000-0002-2147-370X], Novelli, Flavia [0000-0002-3746-7478], Oberst, Andrew [0000-0002-9500-7912], Ofengeim, Dimitry [0000-0003-2348-3642], Opferman, Joseph T. [0000-0002-1147-5621], Oren, Moshe [0000-0003-4311-7172], Pagano, Michele [0000-0003-3210-2442], Panaretakis, Theocharis [0000-0001-5754-6950], Pasparakis, Manolis [0000-0002-9870-0966], Penninger, Josef M. [0000-0002-8194-3777], Pentimalli, Francesca [0000-0003-4740-6801], Pereira, David M. [0000-0003-0384-7592], Pervaiz, Shazib [0000-0002-4738-019X], Peter, Marcus E. [0000-0003-3216-036X], Pinton, Paolo [0000-0001-7108-6508], Porta, Giovanni [0000-0001-5260-2415], Puthalakath, Hamsa [0000-0001-5178-1175], Rabinovich, Gabriel A. [0000-0002-0947-8735], Rajalingam, Krishnaraj [0000-0002-4175-9633], Ravinchandran, Kodi S. [0000-0001-9049-1410], Rehm, Markus [0000-0001-6149-9261], Ricci, Jean-Ehrland [0000-0003-1585-8117], Rizzuto, Rosario [0000-0001-7044-5097], Robinson, Nirmal [0000-0002-7361-9491], Rotblat, Barak [0000-0003-2985-7115], Rothlin, Carla V. [0000-0002-5693-5572], Rubinsztein, David C. [0000-0001-5002-5263], Rufini, Alessandro [0000-0002-5855-655X], Ryan, Kevin M. [0000-0002-1059-9681], Sarosiek, Kristopher A. [0000-0002-4618-5085], Sawa, Akira [0000-0003-1401-3008], Sayan, Emre [0000-0002-5291-1485], Schroder, Kate [0000-0001-9261-3805], Scorrano, Luca [0000-0002-8515-8928], Sesti, Federico [0000-0002-2761-9693], Shi, Yufang [0000-0001-8964-319X], Sica, Giuseppe [0000-0002-7407-0584], Silke, John [0000-0002-7611-5774], Simon, Hans-Uwe [0000-0002-9404-7736], Sistigu, Antonella [0000-0002-2528-1238], Stockwell, Brent R. [0000-0002-3532-3868], Strappazzon, Flavie [0000-0003-0285-7449], Sun, Liming [0000-0002-0136-5605], Sun, Erwei [0000-0001-5664-513X], Szabadkai, G [0000-0002-3006-3577], Tait, Stephen W. G. [0000-0001-7697-132X], Tang, Daolin [0000-0002-1903-6180], Tavernarakis, Nektarios [0000-0002-5253-1466], Turk, Boris [0000-0002-9007-5764], Urbano, Nicoletta [0000-0003-1822-155X], Vandenabeele, Peter [0000-0002-6669-8822], Vanden Berghe, Tom [0000-0002-1633-0974], Vander Heiden, Matthew G. [0000-0002-6702-4192], Vanderluit, Jacqueline L. [0000-0002-4960-920X], Verkhratsky, A. [0000-0003-2592-9898], Villunger, Andreas [0000-0001-8259-4153], Von Karstedt, Silvia [0000-0002-7816-5919], Voss, Anne K. [0000-0002-3853-9381], Vucic, Domagoj [0000-0003-3614-8093], Vuri, Daniela [0000-0001-8693-3845], Wagner, Erwin F. [0000-0001-7872-0196], Walczak, Henning [0000-0002-6312-4591], Wallach, David [0000-0003-2724-9757], Wang, Ruoning [0000-0001-9798-8032], Weber, Achim [0000-0003-0073-3637], Yamazaki, Takahiro [0000-0002-7420-4394], Zakeri, Zahra [0000-0003-4386-8072], Zawacka-Pankau, Joanna E. [0000-0002-7415-2942], Zhivotovsky, Boris [0000-0002-2238-3482], Piacentini, Mauro [0000-0003-2919-1296], Kroemer, Guido [0000-0002-9334-4405], Galluzzi, Lorenzo [0000-0003-2257-8500 ], Vitale, Ilio, Pietrocola, Federico, Guilbaud, Emma, Aaronson, Stuart A., Abrams, John M., Dieter, Adam, Agostini, Massimiliano, Agostinis, Patrizia, Alnemri, Emad S., Altucci, Lucia, Amelio, Ivano, Andrews, David W., Aqeilan, Rami I., Arama, Eli, Baehrecke, Eric H., Balachandran, Siddharth, Bano, Daniele, Barlev, Nickolai A., Bartek, Jiri, Bazan, Nicolas G., Becker, Christoph, Bernassola, Francesca, Bertrand, Mathieu J. M., Bianchi, Marco Emilio, Blagosklonny, Mikhail V., Blander, J. Magarian, Blandino, Giovanni, Blomgren, Klas, Bomer, Christoph, Bortner, Carl D., Bove, Pierluigi, Boya, Patricia, Brenner, Catherine, Broz, Petr, Brunner, T., Damgaard, Rune Busk, Calin, George A., Campanella, Michelangelo, Candi, Eleonora, Carbone, Michele, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K.-M., Chen, Guo‑Qiang, Chen, Quan, Chen, Youhai H., Cheng, Emily H., Chipuk, Jerry E., Cidlowski, John A., Ciechanover, Aaron, Ciliberto, Gennaro, Conrad, Marcus, Cubillos-Ruiz, Juan R., Czabotar, Peter E., D’Angiolella, Vincenzo, Daugaard, Mads, Dawson, Ted M., Dawson, Valina L., De Maria, Ruggero, De Strooper, B., Debatin, Klaus-Michael, Deberardinis, Ralph J., Degterev, Alexei, Del Sal, Giannino, Deshmukh, Mohanish, Di Virgilio, Francesco, Diederich, Marc, Dixon, Scott J., Dynlacht, Brian D., El-Deiry, Wafik S., Elrod, John W., Engeland, Kurt, Fimia, Gian María, Galassi, Claudia, Ganini, Carlo, García-Sáez, Ana J., Garg, Abhishek D., Garrido, Carmen, Gavathiotis, Evripidis, Gerlic, Motti, Ghosh, Sourav, Green, Douglas R., Greene, Lloyd A., Gronemeyer, Hinrich, Häcker, Georg, Hajnóczky, György, Hardwick, J. Marie, Haupt, Ygal, He, Sudan, Heery, David M., Hengartner, Michael O., Hetz, Claudio, Hildeman, David A., Ichijo, Hidenori, Inoue, Satoshi, Jäättelä, Marja, Janic, Ana, Joseph, Bertrand, Jost, Philipp J., Kanneganti, Thirumala-Devi, Karin, Michael, Kashkar, Hamid, Kaufmann, Thomas, Kelly, Gemma L., Kepp, Oliver, Kimchi, Adi, Kitsis, Richard N., Klionsky, Daniel J., Kluck, Ruth, Krysko, Dmitri V., Kulms, Dagmar, Kumar, Sharad, Lavandero, Sergio, Lavrik, Inna N., Lemasters, John J., Liccardi, Gianmaria, Linkermann, Andreas, Lipton, Stuart A., Lockshin, Richard A., López-Otín, Carlos, Luedde, Tom, MacFarlane, Marion, Madeo, Frank, Malorni, Walter, Manic, Gwenola, Mantovani, Roberto, Marchi, Saverio, Marine, Jean-Christophe, Martin, Seamus J., Martinou, Jean-Claude, Mastroberardino, Pier G., Medema, Jan Paul, Mehlen, Patrick, Meier, Pascal, Melino, Gerry, Melino, Sonia, Miao, Edward A., Moll, Ute M., Muñoz-Pinedo, Cristina, Murphy, Daniel J., Niklison-Chirou, Maria Victoria, Novelli, Flavia, Núñez, Gabriel, Oberst, Andrew, Ofengeim, Dimitry, Opferman, Joseph T., Oren, Moshe, Pagano, Michele, Panaretakis, Theocharis, Pasparakis, Manolis, Penninger, Josef M., Pentimalli, Francesca, Pereira, David M., Pervaiz, Shazib, Peter, Marcus E., Pinton, Paolo, Porta, Giovanni, Prehn, Jochen H. M., Puthalakath, Hamsa, Rabinovich, Gabriel A., Rajalingam, Krishnaraj, Ravinchandran, Kodi S., Rehm, Markus, Ricci, Jean-Ehrland, Rizzuto, Rosario, Robinson, Nirmal, Rodrigues, Cecilia M. P., Rotblat, Barak, Rothlin, Carla V., Rubinsztein, David C., Rudel, Thomas, Rufini, Alessandro, Ryan, Kevin M., Sarosiek, Kristopher A., Sawa, Akira, Sayan, Emre, Schroder, Kate, Scorrano, Luca, Sesti, Federico, Shao, Feng, Shi, Yufang, Sica, Giuseppe, Silke, John, Simon, Hans-Uwe, Sistigu, Antonella, Stephanou, Anastasis, Stockwell, Brent R., Strappazzon, Flavie, Strasser, Andreas, Sun, Liming, Sun, Erwei, Sun, Qiang, Szabadkai, G, Tait, Stephen W. G., Tang, Daolin, Tavernarakis, Nektarios, Troy, Carol M., Turk, Boris, Urbano, Nicoletta, Vandenabeele, Peter, Vanden Berghe, Tom, Vander Heiden, Matthew G., Vanderluit, Jacqueline L., Verkhratsky, A., Villunger, Andreas, Von Karstedt, Silvia, Voss, Anne K., Vousden, Karen H., Vucic, Domagoj, Vuri, Daniela, Wagner, Erwin F., Walczak, Henning, Wallach, David, Wang, Ruoning, Wang, Ying, Weber, Achim, Wood, Will, Yamazaki, Takahiro, Yang, Zahra, Zakeri, Zahra, Zawacka-Pankau, Joanna E., Zhang, Lin, Zhang, Haibin, Zhivotovsky, Boris, Zhou, Wenzhao, Piacentini, Mauro, Kroemer, Guido, Galluzzi, Lorenzo, Associazione Italiana per la Ricerca sul Cancro, Italian Institute for Genomic Medicine, Compagnia di San Paolo, Vitale, Ilio [0000-0002-5918-1841], Pietrocola, Federico [0000-0002-2930-234X], Guilbaud, Emma [0000-0001-5261-1944], Aaronson, Stuart A. [0000-0002-4643-0474], Dieter, Adam [0000-0002-5668-5032], Agostini, Massimiliano [0000-0003-3124-2072], Agostinis, Patrizia [0000-0003-1314-2115], Alnemri, Emad S. [0000-0002-7295-3383], Altucci, Lucia [0000-0002-7312-5387], Amelio, Ivano [0000-0002-9126-5391], Andrews, David W. [0000-0002-9266-7157], Aqeilan, Rami I. [0000-0002-6034-023X], Arama, Eli [0000-0001-5953-0629], Balachandran, Siddharth [0000-0003-2084-1803], Bano, Daniele [0000-0002-9617-5504], Bartek, Jiri [0000-0003-2013-7525], Bazan, Nicolas G. [0000-0002-9243-5444], Bernassola, Francesca [0000-0002-8883-8654], Bertrand, Mathieu J. M. [0000-0001-9000-0626], Bianchi, Marco Emilio [0000-0002-5329-6445], Blander, J. Magarian [0000-0001-9207-1700], Blandino, Giovanni [0000-0002-6970-2241], Blomgren, Klas [0000-0002-0476-7271], Bortner, Carl D. [0000-0002-5444-6628], Bove, Pierluigi [0000-0002-4788-2982], Boya, Patricia [0000-0003-3045-951X], Broz, Petr [0000-0002-2334-7790], Damgaard, Rune Busk [0000-0002-1709-6534], Calin, George A. [0000-0002-7427-0578], Campanella, Michelangelo [0000-0002-6948-4184], Candi, Eleonora [0000-0001-8332-4825], Carbone, Michele [0000-0001-8928-8474], Carmona-Gutierrez, Didac [0000-0001-7548-7771], Cecconi, Francesco [0000-0002-5614-4359], Chen, Guo‑Qiang [0000-0002-7226-1782], Cheng, Emily H. [0000-0002-3595-2648], Chipuk, Jerry E. [0000-0002-1337-842X], Cidlowski, John A. [0000-0003-1420-0516], Ciechanover, Aaron [0000-0001-9184-8944], Ciliberto, Gennaro [0000-0003-2851-8605], Conrad, Marcus [0000-0003-1140-5612], Czabotar, Peter E. [0000-0002-2594-496X], D’Angiolella, Vincenzo [0000-0001-8365-9094], Daugaard, Mads [0000-0001-8383-055X], Dawson, Valina L. [0000-0002-2915-3970], De Maria, Ruggero [0000-0003-2255-0583], Debatin, Klaus-Michael [0000-0002-8397-1886], Deberardinis, Ralph J. [0000-0002-2705-7432], Degterev, Alexei [0000-0002-8240-7132], Del Sal, Giannino [0000-0003-2185-6003], Deshmukh, Mohanish [0000-0002-2597-5862], Di Virgilio, Francesco [0000-0003-3566-1362], Diederich, Marc [0000-0003-0115-4725], Dixon, Scott J. [0000-0001-6230-8199], El-Deiry, Wafik S. [0000-0002-9577-8266], Elrod, John W. [0000-0003-3925-2224], Engeland, Kurt [0000-0003-3525-0440], Fimia, Gian María [0000-0003-4438-3325], Ganini, Carlo [0000-0002-5839-3965], García-Sáez, Ana J. [0000-0002-3894-5945], Garg, Abhishek D. [0000-0002-9976-9922], Garrido, Carmen [0000-0003-1368-1493], Gavathiotis, Evripidis [0000-0001-6319-8331], Ghosh, Sourav [0000-0001-5990-8708], Green, Douglas R. [0000-0002-7332-1417], Gronemeyer, Hinrich [0000-0001-9454-2449}, Häcker, Georg [0000-0003-1058-5746], Hajnóczky, György [0000-0003-3813-2570], Hardwick, J. Marie [0000-0002-4847-2045], Haupt, Ygal [0000-0001-5925-0096], He, Sudan [0000-0002-0846-1210], Heery, David M. [0000-0002-5035-2392], Hengartner, Michael O. [0000-0002-7584-596X], Hetz, Claudio [0000-0003-1120-7966], Hildeman, David A. [0000-0002-0421-8483], Ichijo, Hidenori [0000-0002-5005-6438], Jäättelä, Marja [0000-0001-5950-7111], Janic, Ana [0000-0002-4200-2560], Joseph, Bertrand [0000-0001-5655-9979], Jost, Philipp J. [0000-0003-2454-0362], Kanneganti, Thirumala-Devi [0000-0002-6395-6443], Karin, Michael [0000-0002-2758-6473], Kashkar, Hamid [0000-0003-2796-1429], Kaufmann, Thomas [0000-0001-9906-874X], Kelly, Gemma L. [0000-0002-6533-1201], Kepp, Oliver [0000-0002-6081-9558], Kimchi, Adi [0000-0002-8236-8989], Klionsky, Daniel J. [0000-0002-7828-8118], Kluck, Ruth [0000-0002-7101-1925], Krysko, Dmitri V. [0000-0002-9692-2047], Kulms, Dagmar [0000-0001-6874-0548], Kumar, Sharad [0000-0001-7126-9814], Lavandero, Sergio [0000-0003-4258-1483], Lavrik, Inna N. [0000-0002-9324-309X], Liccardi, Gianmaria [0000-0002-2662-1281], Linkermann, Andreas [0000-0001-6287-9725], Lipton, Stuart A. [0000-0002-3490-1259], Lockshin, Richard A. [0000-0002-4389-4898], López-Otín, Carlos [0000-0001-6964-1904], Luedde, Tom [0000-0002-6288-8821], MacFarlane, Marion [0000-0001-7886-1159], Madeo, Frank [0000-0002-5070-1329], Malorni, Walter [0000-0002-1223-7000], Manic, Gwenola [0000-0003-3759-8029], Marchi, Saverio [0000-0003-2708-1843], Marine, Jean-Christophe [0000-0003-2433-9837], Martin, Seamus J. [0000-0002-8539-3143], Martinou, Jean-Claude [0000-0002-9847-2051], Mastroberardino, Pier G. [0000-0003-2364-4258], Medema, Jan Paul [0000-0003-3045-2924], Mehlen, Patrick [0000-0003-1743-5417], Meier, Pascal [0000-0003-2760-6523], Melino, Gerry [0000-0001-9428-5972], Melino, Sonia [0000-0001-7694-5279], Miao, Edward A. [0000-0001-7295-3490], Moll, Ute M. [0000-0003-1908-7516], Muñoz-Pinedo, Cristina [0000-0002-9120-664X], Murphy, Daniel J. [0000-0002-5538-5468], Niklison-Chirou, Maria Victoria [0000-0002-2147-370X], Novelli, Flavia [0000-0002-3746-7478], Oberst, Andrew [0000-0002-9500-7912], Ofengeim, Dimitry [0000-0003-2348-3642], Opferman, Joseph T. [0000-0002-1147-5621], Oren, Moshe [0000-0003-4311-7172], Pagano, Michele [0000-0003-3210-2442], Panaretakis, Theocharis [0000-0001-5754-6950], Pasparakis, Manolis [0000-0002-9870-0966], Penninger, Josef M. [0000-0002-8194-3777], Pentimalli, Francesca [0000-0003-4740-6801], Pereira, David M. [0000-0003-0384-7592], Pervaiz, Shazib [0000-0002-4738-019X], Peter, Marcus E. [0000-0003-3216-036X], Pinton, Paolo [0000-0001-7108-6508], Porta, Giovanni [0000-0001-5260-2415], Puthalakath, Hamsa [0000-0001-5178-1175], Rabinovich, Gabriel A. [0000-0002-0947-8735], Rajalingam, Krishnaraj [0000-0002-4175-9633], Ravinchandran, Kodi S. [0000-0001-9049-1410], Rehm, Markus [0000-0001-6149-9261], Ricci, Jean-Ehrland [0000-0003-1585-8117], Rizzuto, Rosario [0000-0001-7044-5097], Robinson, Nirmal [0000-0002-7361-9491], Rotblat, Barak [0000-0003-2985-7115], Rothlin, Carla V. [0000-0002-5693-5572], Rubinsztein, David C. [0000-0001-5002-5263], Rufini, Alessandro [0000-0002-5855-655X], Ryan, Kevin M. [0000-0002-1059-9681], Sarosiek, Kristopher A. [0000-0002-4618-5085], Sawa, Akira [0000-0003-1401-3008], Sayan, Emre [0000-0002-5291-1485], Schroder, Kate [0000-0001-9261-3805], Scorrano, Luca [0000-0002-8515-8928], Sesti, Federico [0000-0002-2761-9693], Shi, Yufang [0000-0001-8964-319X], Sica, Giuseppe [0000-0002-7407-0584], Silke, John [0000-0002-7611-5774], Simon, Hans-Uwe [0000-0002-9404-7736], Sistigu, Antonella [0000-0002-2528-1238], Stockwell, Brent R. [0000-0002-3532-3868], Strappazzon, Flavie [0000-0003-0285-7449], Sun, Liming [0000-0002-0136-5605], Sun, Erwei [0000-0001-5664-513X], Szabadkai, G [0000-0002-3006-3577], Tait, Stephen W. G. [0000-0001-7697-132X], Tang, Daolin [0000-0002-1903-6180], Tavernarakis, Nektarios [0000-0002-5253-1466], Turk, Boris [0000-0002-9007-5764], Urbano, Nicoletta [0000-0003-1822-155X], Vandenabeele, Peter [0000-0002-6669-8822], Vanden Berghe, Tom [0000-0002-1633-0974], Vander Heiden, Matthew G. [0000-0002-6702-4192], Vanderluit, Jacqueline L. [0000-0002-4960-920X], Verkhratsky, A. [0000-0003-2592-9898], Villunger, Andreas [0000-0001-8259-4153], Von Karstedt, Silvia [0000-0002-7816-5919], Voss, Anne K. [0000-0002-3853-9381], Vucic, Domagoj [0000-0003-3614-8093], Vuri, Daniela [0000-0001-8693-3845], Wagner, Erwin F. [0000-0001-7872-0196], Walczak, Henning [0000-0002-6312-4591], Wallach, David [0000-0003-2724-9757], Wang, Ruoning [0000-0001-9798-8032], Weber, Achim [0000-0003-0073-3637], Yamazaki, Takahiro [0000-0002-7420-4394], Zakeri, Zahra [0000-0003-4386-8072], Zawacka-Pankau, Joanna E. [0000-0002-7415-2942], Zhivotovsky, Boris [0000-0002-2238-3482], Piacentini, Mauro [0000-0003-2919-1296], Kroemer, Guido [0000-0002-9334-4405], Galluzzi, Lorenzo [0000-0003-2257-8500 ], Vitale, Ilio, Pietrocola, Federico, Guilbaud, Emma, Aaronson, Stuart A., Abrams, John M., Dieter, Adam, Agostini, Massimiliano, Agostinis, Patrizia, Alnemri, Emad S., Altucci, Lucia, Amelio, Ivano, Andrews, David W., Aqeilan, Rami I., Arama, Eli, Baehrecke, Eric H., Balachandran, Siddharth, Bano, Daniele, Barlev, Nickolai A., Bartek, Jiri, Bazan, Nicolas G., Becker, Christoph, Bernassola, Francesca, Bertrand, Mathieu J. M., Bianchi, Marco Emilio, Blagosklonny, Mikhail V., Blander, J. Magarian, Blandino, Giovanni, Blomgren, Klas, Bomer, Christoph, Bortner, Carl D., Bove, Pierluigi, Boya, Patricia, Brenner, Catherine, Broz, Petr, Brunner, T., Damgaard, Rune Busk, Calin, George A., Campanella, Michelangelo, Candi, Eleonora, Carbone, Michele, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K.-M., Chen, Guo‑Qiang, Chen, Quan, Chen, Youhai H., Cheng, Emily H., Chipuk, Jerry E., Cidlowski, John A., Ciechanover, Aaron, Ciliberto, Gennaro, Conrad, Marcus, Cubillos-Ruiz, Juan R., Czabotar, Peter E., D’Angiolella, Vincenzo, Daugaard, Mads, Dawson, Ted M., Dawson, Valina L., De Maria, Ruggero, De Strooper, B., Debatin, Klaus-Michael, Deberardinis, Ralph J., Degterev, Alexei, Del Sal, Giannino, Deshmukh, Mohanish, Di Virgilio, Francesco, Diederich, Marc, Dixon, Scott J., Dynlacht, Brian D., El-Deiry, Wafik S., Elrod, John W., Engeland, Kurt, Fimia, Gian María, Galassi, Claudia, Ganini, Carlo, García-Sáez, Ana J., Garg, Abhishek D., Garrido, Carmen, Gavathiotis, Evripidis, Gerlic, Motti, Ghosh, Sourav, Green, Douglas R., Greene, Lloyd A., Gronemeyer, Hinrich, Häcker, Georg, Hajnóczky, György, Hardwick, J. Marie, Haupt, Ygal, He, Sudan, Heery, David M., Hengartner, Michael O., Hetz, Claudio, Hildeman, David A., Ichijo, Hidenori, Inoue, Satoshi, Jäättelä, Marja, Janic, Ana, Joseph, Bertrand, Jost, Philipp J., Kanneganti, Thirumala-Devi, Karin, Michael, Kashkar, Hamid, Kaufmann, Thomas, Kelly, Gemma L., Kepp, Oliver, Kimchi, Adi, Kitsis, Richard N., Klionsky, Daniel J., Kluck, Ruth, Krysko, Dmitri V., Kulms, Dagmar, Kumar, Sharad, Lavandero, Sergio, Lavrik, Inna N., Lemasters, John J., Liccardi, Gianmaria, Linkermann, Andreas, Lipton, Stuart A., Lockshin, Richard A., López-Otín, Carlos, Luedde, Tom, MacFarlane, Marion, Madeo, Frank, Malorni, Walter, Manic, Gwenola, Mantovani, Roberto, Marchi, Saverio, Marine, Jean-Christophe, Martin, Seamus J., Martinou, Jean-Claude, Mastroberardino, Pier G., Medema, Jan Paul, Mehlen, Patrick, Meier, Pascal, Melino, Gerry, Melino, Sonia, Miao, Edward A., Moll, Ute M., Muñoz-Pinedo, Cristina, Murphy, Daniel J., Niklison-Chirou, Maria Victoria, Novelli, Flavia, Núñez, Gabriel, Oberst, Andrew, Ofengeim, Dimitry, Opferman, Joseph T., Oren, Moshe, Pagano, Michele, Panaretakis, Theocharis, Pasparakis, Manolis, Penninger, Josef M., Pentimalli, Francesca, Pereira, David M., Pervaiz, Shazib, Peter, Marcus E., Pinton, Paolo, Porta, Giovanni, Prehn, Jochen H. M., Puthalakath, Hamsa, Rabinovich, Gabriel A., Rajalingam, Krishnaraj, Ravinchandran, Kodi S., Rehm, Markus, Ricci, Jean-Ehrland, Rizzuto, Rosario, Robinson, Nirmal, Rodrigues, Cecilia M. P., Rotblat, Barak, Rothlin, Carla V., Rubinsztein, David C., Rudel, Thomas, Rufini, Alessandro, Ryan, Kevin M., Sarosiek, Kristopher A., Sawa, Akira, Sayan, Emre, Schroder, Kate, Scorrano, Luca, Sesti, Federico, Shao, Feng, Shi, Yufang, Sica, Giuseppe, Silke, John, Simon, Hans-Uwe, Sistigu, Antonella, Stephanou, Anastasis, Stockwell, Brent R., Strappazzon, Flavie, Strasser, Andreas, Sun, Liming, Sun, Erwei, Sun, Qiang, Szabadkai, G, Tait, Stephen W. G., Tang, Daolin, Tavernarakis, Nektarios, Troy, Carol M., Turk, Boris, Urbano, Nicoletta, Vandenabeele, Peter, Vanden Berghe, Tom, Vander Heiden, Matthew G., Vanderluit, Jacqueline L., Verkhratsky, A., Villunger, Andreas, Von Karstedt, Silvia, Voss, Anne K., Vousden, Karen H., Vucic, Domagoj, Vuri, Daniela, Wagner, Erwin F., Walczak, Henning, Wallach, David, Wang, Ruoning, Wang, Ying, Weber, Achim, Wood, Will, Yamazaki, Takahiro, Yang, Zahra, Zakeri, Zahra, Zawacka-Pankau, Joanna E., Zhang, Lin, Zhang, Haibin, Zhivotovsky, Boris, Zhou, Wenzhao, Piacentini, Mauro, Kroemer, Guido, and Galluzzi, Lorenzo
Abstract: Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.
Published: 2023

3. Hidden networks of aberrant protein transnitrosylation contribute to synapse loss in Alzheimer's disease.

Author: Lipton, Stuart A, Lipton, Stuart A, Lipton, Stuart A, and Lipton, Stuart A
Abstract: Emerging evidence indicates the importance of S-nitrosation in regulating protein function and activity. This chemical reaction has been termed protein S-nitrosylation to emphasize its biological importance as a posttranslational modification, in some ways reminiscent of phosphorylation. The reaction at cysteine thiols is distinct from other chemical reactions of nitric oxide (NO) that activate soluble guanylate cyclase via nitrosylation of heme or formation of peroxynitrite via reaction with superoxide anion to produce tyrosine nitration. Here, we review the importance of pathological, aberrant transnitrosylation reactions, i.e., transfer of the NO group from one protein to another, and its consequent effect on the pathogenesis of neurological disorders, to date on Alzheimer's disease (AD), but also expected to affect Parkinson's disease (PD)/Lewy body dementia (LBD), HIV-associated neurocognitive disorder (HAND), and other neurodegenerative and neurodevelopmental disorders.
Published: 2022

4. Towards development of disease-modifying therapy for Alzheimer's disease using redox chemical biology pathways.

Author: Lipton, Stuart A, Lipton, Stuart A, Lipton, Stuart A, and Lipton, Stuart A
Abstract: Redox modifications are described that can be harnessed for the treatment of neurodegenerative disorders, including Alzheimer's disease (AD). The approach has shown potential therapeutic efficacy in AD in both transgenic mouse and hiPSC cerebral organoids models. In this review, two such redox targets are highlighted. First, protein S-nitrosylation of the NMDA-type of glutamate receptor is described as a potential therapeutic target. Second, an S-alkylation reaction of critical, redox-active cysteine thiol(s) on the protein KEAP1 to activate the anti-oxidant/anti-inflammatory transcription factor NRF2 is proposed. In both approaches, we utilize compounds described as pathologically activated therapeutics (or "PAT" drugs), which can only be activated by the disease process that they then combat. Thus, PAT drugs remain relatively innocuous and therefore clinically-tolerated in normal tissue in the absence of disease, thereby avoiding severe side effects both systemically and in the brain.
Published: 2022

5. Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection.

Author: Oh, Chang-Ki, Oh, Chang-Ki, Nakamura, Tomohiro, Beutler, Nathan, Zhang, Xu, Piña-Crespo, Juan, Talantova, Maria, Ghatak, Swagata, Trudler, Dorit, Carnevale, Lauren N, McKercher, Scott R, Bakowski, Malina A, Diedrich, Jolene K, Roberts, Amanda J, Woods, Ashley K, Chi, Victor, Gupta, Anil K, Rosenfeld, Mia A, Kearns, Fiona L, Casalino, Lorenzo, Shaabani, Namir, Liu, Hejun, Wilson, Ian A, Amaro, Rommie E, Burton, Dennis R, Yates, John R, Becker, Cyrus, Rogers, Thomas F, Chatterjee, Arnab K, Lipton, Stuart A, Oh, Chang-Ki, Oh, Chang-Ki, Nakamura, Tomohiro, Beutler, Nathan, Zhang, Xu, Piña-Crespo, Juan, Talantova, Maria, Ghatak, Swagata, Trudler, Dorit, Carnevale, Lauren N, McKercher, Scott R, Bakowski, Malina A, Diedrich, Jolene K, Roberts, Amanda J, Woods, Ashley K, Chi, Victor, Gupta, Anil K, Rosenfeld, Mia A, Kearns, Fiona L, Casalino, Lorenzo, Shaabani, Namir, Liu, Hejun, Wilson, Ian A, Amaro, Rommie E, Burton, Dennis R, Yates, John R, Becker, Cyrus, Rogers, Thomas F, Chatterjee, Arnab K, and Lipton, Stuart A
Abstract: Prevention of infection and propagation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a high priority in the Coronavirus Disease 2019 (COVID-19) pandemic. Here we describe S-nitrosylation of multiple proteins involved in SARS-CoV-2 infection, including angiotensin-converting enzyme 2 (ACE2), the receptor for viral entry. This reaction prevents binding of ACE2 to the SARS-CoV-2 spike protein, thereby inhibiting viral entry, infectivity and cytotoxicity. Aminoadamantane compounds also inhibit coronavirus ion channels formed by envelope (E) protein. Accordingly, we developed dual-mechanism aminoadamantane nitrate compounds that inhibit viral entry and, thus, the spread of infection by S-nitrosylating ACE2 via targeted delivery of the drug after E protein channel blockade. These non-toxic compounds are active in vitro and in vivo in the Syrian hamster COVID-19 model and, thus, provide a novel avenue to pursue therapy.
Published: 2023

6. Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis.

Author: Okuda, Kosaku, Okuda, Kosaku, Nakahara, Kengo, Ito, Akihiro, Iijima, Yuta, Nomura, Ryosuke, Kumar, Ashutosh, Fujikawa, Kana, Adachi, Kazuya, Shimada, Yuki, Fujio, Satoshi, Yamamoto, Reina, Takasugi, Nobumasa, Onuma, Kunishige, Osaki, Mitsuhiko, Okada, Futoshi, Ukegawa, Taichi, Takeuchi, Yasuo, Yasui, Norihisa, Yamashita, Atsuko, Marusawa, Hiroyuki, Matsushita, Yosuke, Katagiri, Toyomasa, Shibata, Takahiro, Uchida, Koji, Niu, Sheng-Yong, Lang, Nhi B, Nakamura, Tomohiro, Zhang, Kam YJ, Lipton, Stuart A, Uehara, Takashi, Okuda, Kosaku, Okuda, Kosaku, Nakahara, Kengo, Ito, Akihiro, Iijima, Yuta, Nomura, Ryosuke, Kumar, Ashutosh, Fujikawa, Kana, Adachi, Kazuya, Shimada, Yuki, Fujio, Satoshi, Yamamoto, Reina, Takasugi, Nobumasa, Onuma, Kunishige, Osaki, Mitsuhiko, Okada, Futoshi, Ukegawa, Taichi, Takeuchi, Yasuo, Yasui, Norihisa, Yamashita, Atsuko, Marusawa, Hiroyuki, Matsushita, Yosuke, Katagiri, Toyomasa, Shibata, Takahiro, Uchida, Koji, Niu, Sheng-Yong, Lang, Nhi B, Nakamura, Tomohiro, Zhang, Kam YJ, Lipton, Stuart A, and Uehara, Takashi
Abstract: DNA methyltransferases (DNMTs) catalyze methylation at the C5 position of cytosine with S-adenosyl-L-methionine. Methylation regulates gene expression, serving a variety of physiological and pathophysiological roles. The chemical mechanisms regulating DNMT enzymatic activity, however, are not fully elucidated. Here, we show that protein S-nitrosylation of a cysteine residue in DNMT3B attenuates DNMT3B enzymatic activity and consequent aberrant upregulation of gene expression. These genes include Cyclin D2 (Ccnd2), which is required for neoplastic cell proliferation in some tumor types. In cell-based and in vivo cancer models, only DNMT3B enzymatic activity, and not DNMT1 or DNMT3A, affects Ccnd2 expression. Using structure-based virtual screening, we discovered chemical compounds that specifically inhibit S-nitrosylation without directly affecting DNMT3B enzymatic activity. The lead compound, designated DBIC, inhibits S-nitrosylation of DNMT3B at low concentrations (IC50 ≤ 100 nM). Treatment with DBIC prevents nitric oxide (NO)-induced conversion of human colonic adenoma to adenocarcinoma in vitro. Additionally, in vivo treatment with DBIC strongly attenuates tumor development in a mouse model of carcinogenesis triggered by inflammation-induced generation of NO. Our results demonstrate that de novo DNA methylation mediated by DNMT3B is regulated by NO, and DBIC protects against tumor formation by preventing aberrant S-nitrosylation of DNMT3B.
Published: 2023

7. Aberrant protein S-nitrosylation contributes to hyperexcitability-induced synaptic damage in Alzheimer's disease: Mechanistic insights and potential therapies.

Author: Ghatak, Swagata, Ghatak, Swagata, Nakamura, Tomohiro, Lipton, Stuart A, Ghatak, Swagata, Ghatak, Swagata, Nakamura, Tomohiro, and Lipton, Stuart A
Abstract: Alzheimer's disease (AD) is arguably the most common cause of dementia in the elderly and is marked by progressive synaptic degeneration, which in turn leads to cognitive decline. Studies in patients and in various AD models have shown that one of the early signatures of AD is neuronal hyperactivity. This excessive electrical activity contributes to dysregulated neural network function and synaptic damage. Mechanistically, evidence suggests that hyperexcitability accelerates production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that contribute to neural network impairment and synapse loss. This review focuses on the pathways and molecular changes that cause hyperexcitability and how RNS-dependent posttranslational modifications, represented predominantly by protein S-nitrosylation, mediate, at least in part, the deleterious effects of hyperexcitability on single neurons and the neural network, resulting in synaptic loss in AD.
Published: 2023

8. Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis

Author: Okuda, Kosaku, Nakahara, Kengo, Ito, Akihiro, Iijima, Yuta, Nomura, Ryosuke, Kumar, Ashutosh, Fujikawa, Kana, Adachi, Kazuya, Shimada, Yuki, Fujio, Satoshi, Yamamoto, Reina, Takasugi, Nobumasa, Onuma, Kunishige, Osaki, Mitsuhiko, Okada, Futoshi, Ukegawa, Taichi, Takeuchi, Yasuo, Yasui, Norihisa, Yamashita, Atsuko, Marusawa, Hiroyuki, Matsushita, Yosuke, Katagiri, Toyomasa, Shibata, Takahiro, Uchida, Koji, Niu, Sheng-Yong, Lang, Nhi B., Nakamura, Tomohiro, Zhang, Kam Y. J., Lipton, Stuart A., Uehara, Takashi, Okuda, Kosaku, Nakahara, Kengo, Ito, Akihiro, Iijima, Yuta, Nomura, Ryosuke, Kumar, Ashutosh, Fujikawa, Kana, Adachi, Kazuya, Shimada, Yuki, Fujio, Satoshi, Yamamoto, Reina, Takasugi, Nobumasa, Onuma, Kunishige, Osaki, Mitsuhiko, Okada, Futoshi, Ukegawa, Taichi, Takeuchi, Yasuo, Yasui, Norihisa, Yamashita, Atsuko, Marusawa, Hiroyuki, Matsushita, Yosuke, Katagiri, Toyomasa, Shibata, Takahiro, Uchida, Koji, Niu, Sheng-Yong, Lang, Nhi B., Nakamura, Tomohiro, Zhang, Kam Y. J., Lipton, Stuart A., and Uehara, Takashi
Abstract: DNA methyltransferases (DNMTs) catalyze methylation at the C5 position of cytosine with S-adenosyl-l-methionine. Methylation regulates gene expression, serving a variety of physiological and pathophysiological roles. The chemical mechanisms regulating DNMT enzymatic activity, however, are not fully elucidated. Here, we show that protein S-nitrosylation of a cysteine residue in DNMT3B attenuates DNMT3B enzymatic activity and consequent aberrant upregulation of gene expression. These genes include Cyclin D2 (Ccnd2), which is required for neoplastic cell proliferation in some tumor types. In cell-based and in vivo cancer models, only DNMT3B enzymatic activity, and not DNMT1 or DNMT3A, affects Ccnd2 expression. Using structure-based virtual screening, we discovered chemical compounds that specifically inhibit S-nitrosylation without directly affecting DNMT3B enzymatic activity. The lead compound, designated DBIC, inhibits S-nitrosylation of DNMT3B at low concentrations (IC50 <= 100nM). Treatment with DBIC prevents nitric oxide (NO)-induced conversion of human colonic adenoma to adenocarcinoma in vitro. Additionally, in vivo treatment with DBIC strongly attenuates tumor development in a mouse model of carcinogenesis triggered by inflammation-induced generation of NO. Our results demonstrate that de novo DNA methylation mediated by DNMT3B is regulated by NO, and DBIC protects against tumor formation by preventing aberrant S-nitrosylation of DNMT3B.
Published: 2023

9. Apoptotic cell death in disease—Current understanding of the NCCD 2023

Author: Vitale, Ilio, Pietrocola, Federico, Guilbaud, Emma, Aaronson, Stuart A., Abrams, John M., Adam, Dieter, Agostini, Massimiliano, Agostinis, Patrizia, Alnemri, Emad S., Altucci, Lucia, Amelio, Ivano, Andrews, David W., Aqeilan, Rami I., Arama, Eli, Baehrecke, Eric H., Balachandran, Siddharth, Bano, Daniele, Barlev, Nickolai A., Bartek, Jiri, Bazan, Nicolas G., Becker, Christoph, Bernassola, Francesca, Bertrand, Mathieu J.M., Bianchi, Marco E., Blagosklonny, Mikhail V., Blander, J. Magarian, Blandino, Giovanni, Blomgren, Klas, Borner, Christoph, Bortner, Carl D., Bove, Pierluigi, Boya, Patricia, Brenner, Catherine, Broz, Petr, Brunner, Thomas, Damgaard, Rune Busk, Calin, George A., Campanella, Michelangelo, Candi, Eleonora, Carbone, Michele, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K.M., Chen, Guo Qiang, Chen, Quan, Chen, Youhai H., Cheng, Emily H., Chipuk, Jerry E., Cidlowski, John A., Ciechanover, Aaron, Ciliberto, Gennaro, Conrad, Marcus, Cubillos-Ruiz, Juan R., Czabotar, Peter E., D’Angiolella, Vincenzo, Daugaard, Mads, Dawson, Ted M., Dawson, Valina L., De Maria, Ruggero, De Strooper, Bart, Debatin, Klaus Michael, Deberardinis, Ralph J., Degterev, Alexei, Del Sal, Giannino, Deshmukh, Mohanish, Di Virgilio, Francesco, Diederich, Marc, Dixon, Scott J., Dynlacht, Brian D., El-Deiry, Wafik S., Elrod, John W., Engeland, Kurt, Fimia, Gian Maria, Galassi, Claudia, Ganini, Carlo, Garcia-Saez, Ana J., Garg, Abhishek D., Garrido, Carmen, Gavathiotis, Evripidis, Gerlic, Motti, Ghosh, Sourav, Green, Douglas R., Greene, Lloyd A., Gronemeyer, Hinrich, Häcker, Georg, Hajnóczky, György, Hardwick, J. Marie, Haupt, Ygal, He, Sudan, Heery, David M., Hengartner, Michael O., Hetz, Claudio, Hildeman, David A., Ichijo, Hidenori, Inoue, Satoshi, Jäättelä, Marja, Janic, Ana, Joseph, Bertrand, Jost, Philipp J., Kanneganti, Thirumala Devi, Karin, Michael, Kashkar, Hamid, Kaufmann, Thomas, Kelly, Gemma L., Kepp, Oliver, Kimchi, Adi, Kitsis, Richard N., Klionsky, Daniel J., Kluck, Ruth, Krysko, Dmitri V., Kulms, Dagmar, Kumar, Sharad, Lavandero, Sergio, Lavrik, Inna N., Lemasters, John J., Liccardi, Gianmaria, Linkermann, Andreas, Lipton, Stuart A., Lockshin, Richard A., López-Otín, Carlos, Luedde, Tom, MacFarlane, Marion, Madeo, Frank, Malorni, Walter, Manic, Gwenola, Mantovani, Roberto, Marchi, Saverio, Marine, Jean Christophe, Martin, Seamus J., Martinou, Jean Claude, Mastroberardino, Pier G., Medema, Jan Paul, Mehlen, Patrick, Meier, Pascal, Melino, Gerry, Melino, Sonia, Miao, Edward A., Moll, Ute M., Muñoz-Pinedo, Cristina, Murphy, Daniel J., Niklison-Chirou, Maria Victoria, Novelli, Flavia, Núñez, Gabriel, Oberst, Andrew, Ofengeim, Dimitry, Opferman, Joseph T., Oren, Moshe, Pagano, Michele, Panaretakis, Theocharis, Pasparakis, Manolis, Penninger, Josef M., Pentimalli, Francesca, Pereira, David M., Pervaiz, Shazib, Peter, Marcus E., Pinton, Paolo, Porta, Giovanni, Prehn, Jochen H.M., Puthalakath, Hamsa, Rabinovich, Gabriel A., Rajalingam, Krishnaraj, Ravichandran, Kodi S., Rehm, Markus, Ricci, Jean Ehrland, Rizzuto, Rosario, Robinson, Nirmal, Rodrigues, Cecilia M.P., Rotblat, Barak, Rothlin, Carla V., Rubinsztein, David C., Rudel, Thomas, Rufini, Alessandro, Ryan, Kevin M., Sarosiek, Kristopher A., Sawa, Akira, Sayan, Emre, Schroder, Kate, Scorrano, Luca, Sesti, Federico, Shao, Feng, Shi, Yufang, Sica, Giuseppe S., Silke, John, Simon, Hans Uwe, Sistigu, Antonella, Stephanou, Anastasis, Stockwell, Brent R., Strapazzon, Flavie, Strasser, Andreas, Sun, Liming, Sun, Erwei, Sun, Qiang, Szabadkai, Gyorgy, Tait, Stephen W.G., Tang, Daolin, Tavernarakis, Nektarios, Troy, Carol M., Turk, Boris, Urbano, Nicoletta, Vandenabeele, Peter, Vanden Berghe, Tom, Vander Heiden, Matthew G., Vanderluit, Jacqueline L., Verkhratsky, Alexei, Villunger, Andreas, von Karstedt, Silvia, Voss, Anne K., Vousden, Karen H., Vucic, Domagoj, Vuri, Daniela, Wagner, Erwin F., Walczak, Henning, Wallach, David, Wang, Ruoning, Wang, Ying, Weber, Achim, Wood, Will, Yamazaki, Takahiro, Yang, Huang Tian, Zakeri, Zahra, Zawacka-Pankau, Joanna E., Zhang, Lin, Zhang, Haibing, Zhivotovsky, Boris, Zhou, Wenzhao, Piacentini, Mauro, Kroemer, Guido, Galluzzi, Lorenzo, Vitale, Ilio, Pietrocola, Federico, Guilbaud, Emma, Aaronson, Stuart A., Abrams, John M., Adam, Dieter, Agostini, Massimiliano, Agostinis, Patrizia, Alnemri, Emad S., Altucci, Lucia, Amelio, Ivano, Andrews, David W., Aqeilan, Rami I., Arama, Eli, Baehrecke, Eric H., Balachandran, Siddharth, Bano, Daniele, Barlev, Nickolai A., Bartek, Jiri, Bazan, Nicolas G., Becker, Christoph, Bernassola, Francesca, Bertrand, Mathieu J.M., Bianchi, Marco E., Blagosklonny, Mikhail V., Blander, J. Magarian, Blandino, Giovanni, Blomgren, Klas, Borner, Christoph, Bortner, Carl D., Bove, Pierluigi, Boya, Patricia, Brenner, Catherine, Broz, Petr, Brunner, Thomas, Damgaard, Rune Busk, Calin, George A., Campanella, Michelangelo, Candi, Eleonora, Carbone, Michele, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K.M., Chen, Guo Qiang, Chen, Quan, Chen, Youhai H., Cheng, Emily H., Chipuk, Jerry E., Cidlowski, John A., Ciechanover, Aaron, Ciliberto, Gennaro, Conrad, Marcus, Cubillos-Ruiz, Juan R., Czabotar, Peter E., D’Angiolella, Vincenzo, Daugaard, Mads, Dawson, Ted M., Dawson, Valina L., De Maria, Ruggero, De Strooper, Bart, Debatin, Klaus Michael, Deberardinis, Ralph J., Degterev, Alexei, Del Sal, Giannino, Deshmukh, Mohanish, Di Virgilio, Francesco, Diederich, Marc, Dixon, Scott J., Dynlacht, Brian D., El-Deiry, Wafik S., Elrod, John W., Engeland, Kurt, Fimia, Gian Maria, Galassi, Claudia, Ganini, Carlo, Garcia-Saez, Ana J., Garg, Abhishek D., Garrido, Carmen, Gavathiotis, Evripidis, Gerlic, Motti, Ghosh, Sourav, Green, Douglas R., Greene, Lloyd A., Gronemeyer, Hinrich, Häcker, Georg, Hajnóczky, György, Hardwick, J. Marie, Haupt, Ygal, He, Sudan, Heery, David M., Hengartner, Michael O., Hetz, Claudio, Hildeman, David A., Ichijo, Hidenori, Inoue, Satoshi, Jäättelä, Marja, Janic, Ana, Joseph, Bertrand, Jost, Philipp J., Kanneganti, Thirumala Devi, Karin, Michael, Kashkar, Hamid, Kaufmann, Thomas, Kelly, Gemma L., Kepp, Oliver, Kimchi, Adi, Kitsis, Richard N., Klionsky, Daniel J., Kluck, Ruth, Krysko, Dmitri V., Kulms, Dagmar, Kumar, Sharad, Lavandero, Sergio, Lavrik, Inna N., Lemasters, John J., Liccardi, Gianmaria, Linkermann, Andreas, Lipton, Stuart A., Lockshin, Richard A., López-Otín, Carlos, Luedde, Tom, MacFarlane, Marion, Madeo, Frank, Malorni, Walter, Manic, Gwenola, Mantovani, Roberto, Marchi, Saverio, Marine, Jean Christophe, Martin, Seamus J., Martinou, Jean Claude, Mastroberardino, Pier G., Medema, Jan Paul, Mehlen, Patrick, Meier, Pascal, Melino, Gerry, Melino, Sonia, Miao, Edward A., Moll, Ute M., Muñoz-Pinedo, Cristina, Murphy, Daniel J., Niklison-Chirou, Maria Victoria, Novelli, Flavia, Núñez, Gabriel, Oberst, Andrew, Ofengeim, Dimitry, Opferman, Joseph T., Oren, Moshe, Pagano, Michele, Panaretakis, Theocharis, Pasparakis, Manolis, Penninger, Josef M., Pentimalli, Francesca, Pereira, David M., Pervaiz, Shazib, Peter, Marcus E., Pinton, Paolo, Porta, Giovanni, Prehn, Jochen H.M., Puthalakath, Hamsa, Rabinovich, Gabriel A., Rajalingam, Krishnaraj, Ravichandran, Kodi S., Rehm, Markus, Ricci, Jean Ehrland, Rizzuto, Rosario, Robinson, Nirmal, Rodrigues, Cecilia M.P., Rotblat, Barak, Rothlin, Carla V., Rubinsztein, David C., Rudel, Thomas, Rufini, Alessandro, Ryan, Kevin M., Sarosiek, Kristopher A., Sawa, Akira, Sayan, Emre, Schroder, Kate, Scorrano, Luca, Sesti, Federico, Shao, Feng, Shi, Yufang, Sica, Giuseppe S., Silke, John, Simon, Hans Uwe, Sistigu, Antonella, Stephanou, Anastasis, Stockwell, Brent R., Strapazzon, Flavie, Strasser, Andreas, Sun, Liming, Sun, Erwei, Sun, Qiang, Szabadkai, Gyorgy, Tait, Stephen W.G., Tang, Daolin, Tavernarakis, Nektarios, Troy, Carol M., Turk, Boris, Urbano, Nicoletta, Vandenabeele, Peter, Vanden Berghe, Tom, Vander Heiden, Matthew G., Vanderluit, Jacqueline L., Verkhratsky, Alexei, Villunger, Andreas, von Karstedt, Silvia, Voss, Anne K., Vousden, Karen H., Vucic, Domagoj, Vuri, Daniela, Wagner, Erwin F., Walczak, Henning, Wallach, David, Wang, Ruoning, Wang, Ying, Weber, Achim, Wood, Will, Yamazaki, Takahiro, Yang, Huang Tian, Zakeri, Zahra, Zawacka-Pankau, Joanna E., Zhang, Lin, Zhang, Haibing, Zhivotovsky, Boris, Zhou, Wenzhao, Piacentini, Mauro, Kroemer, Guido, and Galluzzi, Lorenzo
Abstract: Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.
Published: 2023

10. Apoptotic cell death in disease—Current understanding of the NCCD 2023

Author: Vitale, Ilio, Pietrocola, Federico, Guilbaud, Emma, Aaronson, Stuart A., Abrams, John M., Adam, Dieter, Agostini, Massimiliano, Agostinis, Patrizia, Alnemri, Emad S., Altucci, Lucia, Amelio, Ivano, Andrews, David W., Aqeilan, Rami I., Arama, Eli, Baehrecke, Eric H., Balachandran, Siddharth, Bano, Daniele, Barlev, Nickolai A., Bartek, Jiri, Bazan, Nicolas G., Becker, Christoph, Bernassola, Francesca, Bertrand, Mathieu J.M., Bianchi, Marco E., Blagosklonny, Mikhail V., Blander, J. Magarian, Blandino, Giovanni, Blomgren, Klas, Borner, Christoph, Bortner, Carl D., Bove, Pierluigi, Boya, Patricia, Brenner, Catherine, Broz, Petr, Brunner, Thomas, Damgaard, Rune Busk, Calin, George A., Campanella, Michelangelo, Candi, Eleonora, Carbone, Michele, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K.M., Chen, Guo Qiang, Chen, Quan, Chen, Youhai H., Cheng, Emily H., Chipuk, Jerry E., Cidlowski, John A., Ciechanover, Aaron, Ciliberto, Gennaro, Conrad, Marcus, Cubillos-Ruiz, Juan R., Czabotar, Peter E., D’Angiolella, Vincenzo, Daugaard, Mads, Dawson, Ted M., Dawson, Valina L., De Maria, Ruggero, De Strooper, Bart, Debatin, Klaus Michael, Deberardinis, Ralph J., Degterev, Alexei, Del Sal, Giannino, Deshmukh, Mohanish, Di Virgilio, Francesco, Diederich, Marc, Dixon, Scott J., Dynlacht, Brian D., El-Deiry, Wafik S., Elrod, John W., Engeland, Kurt, Fimia, Gian Maria, Galassi, Claudia, Ganini, Carlo, Garcia-Saez, Ana J., Garg, Abhishek D., Garrido, Carmen, Gavathiotis, Evripidis, Gerlic, Motti, Ghosh, Sourav, Green, Douglas R., Greene, Lloyd A., Gronemeyer, Hinrich, Häcker, Georg, Hajnóczky, György, Hardwick, J. Marie, Haupt, Ygal, He, Sudan, Heery, David M., Hengartner, Michael O., Hetz, Claudio, Hildeman, David A., Ichijo, Hidenori, Inoue, Satoshi, Jäättelä, Marja, Janic, Ana, Joseph, Bertrand, Jost, Philipp J., Kanneganti, Thirumala Devi, Karin, Michael, Kashkar, Hamid, Kaufmann, Thomas, Kelly, Gemma L., Kepp, Oliver, Kimchi, Adi, Kitsis, Richard N., Klionsky, Daniel J., Kluck, Ruth, Krysko, Dmitri V., Kulms, Dagmar, Kumar, Sharad, Lavandero, Sergio, Lavrik, Inna N., Lemasters, John J., Liccardi, Gianmaria, Linkermann, Andreas, Lipton, Stuart A., Lockshin, Richard A., López-Otín, Carlos, Luedde, Tom, MacFarlane, Marion, Madeo, Frank, Malorni, Walter, Manic, Gwenola, Mantovani, Roberto, Marchi, Saverio, Marine, Jean Christophe, Martin, Seamus J., Martinou, Jean Claude, Mastroberardino, Pier G., Medema, Jan Paul, Mehlen, Patrick, Meier, Pascal, Melino, Gerry, Melino, Sonia, Miao, Edward A., Moll, Ute M., Muñoz-Pinedo, Cristina, Murphy, Daniel J., Niklison-Chirou, Maria Victoria, Novelli, Flavia, Núñez, Gabriel, Oberst, Andrew, Ofengeim, Dimitry, Opferman, Joseph T., Oren, Moshe, Pagano, Michele, Panaretakis, Theocharis, Pasparakis, Manolis, Penninger, Josef M., Pentimalli, Francesca, Pereira, David M., Pervaiz, Shazib, Peter, Marcus E., Pinton, Paolo, Porta, Giovanni, Prehn, Jochen H.M., Puthalakath, Hamsa, Rabinovich, Gabriel A., Rajalingam, Krishnaraj, Ravichandran, Kodi S., Rehm, Markus, Ricci, Jean Ehrland, Rizzuto, Rosario, Robinson, Nirmal, Rodrigues, Cecilia M.P., Rotblat, Barak, Rothlin, Carla V., Rubinsztein, David C., Rudel, Thomas, Rufini, Alessandro, Ryan, Kevin M., Sarosiek, Kristopher A., Sawa, Akira, Sayan, Emre, Schroder, Kate, Scorrano, Luca, Sesti, Federico, Shao, Feng, Shi, Yufang, Sica, Giuseppe S., Silke, John, Simon, Hans Uwe, Sistigu, Antonella, Stephanou, Anastasis, Stockwell, Brent R., Strapazzon, Flavie, Strasser, Andreas, Sun, Liming, Sun, Erwei, Sun, Qiang, Szabadkai, Gyorgy, Tait, Stephen W.G., Tang, Daolin, Tavernarakis, Nektarios, Troy, Carol M., Turk, Boris, Urbano, Nicoletta, Vandenabeele, Peter, Vanden Berghe, Tom, Vander Heiden, Matthew G., Vanderluit, Jacqueline L., Verkhratsky, Alexei, Villunger, Andreas, von Karstedt, Silvia, Voss, Anne K., Vousden, Karen H., Vucic, Domagoj, Vuri, Daniela, Wagner, Erwin F., Walczak, Henning, Wallach, David, Wang, Ruoning, Wang, Ying, Weber, Achim, Wood, Will, Yamazaki, Takahiro, Yang, Huang Tian, Zakeri, Zahra, Zawacka-Pankau, Joanna E., Zhang, Lin, Zhang, Haibing, Zhivotovsky, Boris, Zhou, Wenzhao, Piacentini, Mauro, Kroemer, Guido, Galluzzi, Lorenzo, Vitale, Ilio, Pietrocola, Federico, Guilbaud, Emma, Aaronson, Stuart A., Abrams, John M., Adam, Dieter, Agostini, Massimiliano, Agostinis, Patrizia, Alnemri, Emad S., Altucci, Lucia, Amelio, Ivano, Andrews, David W., Aqeilan, Rami I., Arama, Eli, Baehrecke, Eric H., Balachandran, Siddharth, Bano, Daniele, Barlev, Nickolai A., Bartek, Jiri, Bazan, Nicolas G., Becker, Christoph, Bernassola, Francesca, Bertrand, Mathieu J.M., Bianchi, Marco E., Blagosklonny, Mikhail V., Blander, J. Magarian, Blandino, Giovanni, Blomgren, Klas, Borner, Christoph, Bortner, Carl D., Bove, Pierluigi, Boya, Patricia, Brenner, Catherine, Broz, Petr, Brunner, Thomas, Damgaard, Rune Busk, Calin, George A., Campanella, Michelangelo, Candi, Eleonora, Carbone, Michele, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K.M., Chen, Guo Qiang, Chen, Quan, Chen, Youhai H., Cheng, Emily H., Chipuk, Jerry E., Cidlowski, John A., Ciechanover, Aaron, Ciliberto, Gennaro, Conrad, Marcus, Cubillos-Ruiz, Juan R., Czabotar, Peter E., D’Angiolella, Vincenzo, Daugaard, Mads, Dawson, Ted M., Dawson, Valina L., De Maria, Ruggero, De Strooper, Bart, Debatin, Klaus Michael, Deberardinis, Ralph J., Degterev, Alexei, Del Sal, Giannino, Deshmukh, Mohanish, Di Virgilio, Francesco, Diederich, Marc, Dixon, Scott J., Dynlacht, Brian D., El-Deiry, Wafik S., Elrod, John W., Engeland, Kurt, Fimia, Gian Maria, Galassi, Claudia, Ganini, Carlo, Garcia-Saez, Ana J., Garg, Abhishek D., Garrido, Carmen, Gavathiotis, Evripidis, Gerlic, Motti, Ghosh, Sourav, Green, Douglas R., Greene, Lloyd A., Gronemeyer, Hinrich, Häcker, Georg, Hajnóczky, György, Hardwick, J. Marie, Haupt, Ygal, He, Sudan, Heery, David M., Hengartner, Michael O., Hetz, Claudio, Hildeman, David A., Ichijo, Hidenori, Inoue, Satoshi, Jäättelä, Marja, Janic, Ana, Joseph, Bertrand, Jost, Philipp J., Kanneganti, Thirumala Devi, Karin, Michael, Kashkar, Hamid, Kaufmann, Thomas, Kelly, Gemma L., Kepp, Oliver, Kimchi, Adi, Kitsis, Richard N., Klionsky, Daniel J., Kluck, Ruth, Krysko, Dmitri V., Kulms, Dagmar, Kumar, Sharad, Lavandero, Sergio, Lavrik, Inna N., Lemasters, John J., Liccardi, Gianmaria, Linkermann, Andreas, Lipton, Stuart A., Lockshin, Richard A., López-Otín, Carlos, Luedde, Tom, MacFarlane, Marion, Madeo, Frank, Malorni, Walter, Manic, Gwenola, Mantovani, Roberto, Marchi, Saverio, Marine, Jean Christophe, Martin, Seamus J., Martinou, Jean Claude, Mastroberardino, Pier G., Medema, Jan Paul, Mehlen, Patrick, Meier, Pascal, Melino, Gerry, Melino, Sonia, Miao, Edward A., Moll, Ute M., Muñoz-Pinedo, Cristina, Murphy, Daniel J., Niklison-Chirou, Maria Victoria, Novelli, Flavia, Núñez, Gabriel, Oberst, Andrew, Ofengeim, Dimitry, Opferman, Joseph T., Oren, Moshe, Pagano, Michele, Panaretakis, Theocharis, Pasparakis, Manolis, Penninger, Josef M., Pentimalli, Francesca, Pereira, David M., Pervaiz, Shazib, Peter, Marcus E., Pinton, Paolo, Porta, Giovanni, Prehn, Jochen H.M., Puthalakath, Hamsa, Rabinovich, Gabriel A., Rajalingam, Krishnaraj, Ravichandran, Kodi S., Rehm, Markus, Ricci, Jean Ehrland, Rizzuto, Rosario, Robinson, Nirmal, Rodrigues, Cecilia M.P., Rotblat, Barak, Rothlin, Carla V., Rubinsztein, David C., Rudel, Thomas, Rufini, Alessandro, Ryan, Kevin M., Sarosiek, Kristopher A., Sawa, Akira, Sayan, Emre, Schroder, Kate, Scorrano, Luca, Sesti, Federico, Shao, Feng, Shi, Yufang, Sica, Giuseppe S., Silke, John, Simon, Hans Uwe, Sistigu, Antonella, Stephanou, Anastasis, Stockwell, Brent R., Strapazzon, Flavie, Strasser, Andreas, Sun, Liming, Sun, Erwei, Sun, Qiang, Szabadkai, Gyorgy, Tait, Stephen W.G., Tang, Daolin, Tavernarakis, Nektarios, Troy, Carol M., Turk, Boris, Urbano, Nicoletta, Vandenabeele, Peter, Vanden Berghe, Tom, Vander Heiden, Matthew G., Vanderluit, Jacqueline L., Verkhratsky, Alexei, Villunger, Andreas, von Karstedt, Silvia, Voss, Anne K., Vousden, Karen H., Vucic, Domagoj, Vuri, Daniela, Wagner, Erwin F., Walczak, Henning, Wallach, David, Wang, Ruoning, Wang, Ying, Weber, Achim, Wood, Will, Yamazaki, Takahiro, Yang, Huang Tian, Zakeri, Zahra, Zawacka-Pankau, Joanna E., Zhang, Lin, Zhang, Haibing, Zhivotovsky, Boris, Zhou, Wenzhao, Piacentini, Mauro, Kroemer, Guido, and Galluzzi, Lorenzo
Abstract: Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.
Published: 2023

11. Potential Therapeutic Use of the Rosemary Diterpene Carnosic Acid for Alzheimer's Disease, Parkinson's Disease, and Long-COVID through NRF2 Activation to Counteract the NLRP3 Inflammasome.

Author: Satoh, Takumi, Satoh, Takumi, Trudler, Dorit, Oh, Chang-Ki, Lipton, Stuart A, Satoh, Takumi, Satoh, Takumi, Trudler, Dorit, Oh, Chang-Ki, and Lipton, Stuart A
Abstract: Rosemary (Rosmarinus officinalis [family Lamiaceae]), an herb of economic and gustatory repute, is employed in traditional medicines in many countries. Rosemary contains carnosic acid (CA) and carnosol (CS), abietane-type phenolic diterpenes, which account for most of its biological and pharmacological actions, although claims have also been made for contributions of another constituent, rosmarinic acid. This review focuses on the potential applications of CA and CS for Alzheimer's disease (AD), Parkinson's disease (PD), and coronavirus disease 2019 (COVID-19), in part via inhibition of the NLRP3 inflammasome. CA exerts antioxidant, anti-inflammatory, and neuroprotective effects via phase 2 enzyme induction initiated by activation of the KEAP1/NRF2 transcriptional pathway, which in turn attenuates NLRP3 activation. In addition, we propose that CA-related compounds may serve as therapeutics against the brain-related after-effects of SARS-CoV-2 infection, termed "long-COVID." One factor that contributes to COVID-19 is cytokine storm emanating from macrophages as a result of unregulated inflammation in and around lung epithelial and endovascular cells. Additionally, neurological aftereffects such as anxiety and "brain fog" are becoming a major issue for both the pandemic and post-pandemic period. Many reports hold that unregulated NLRP3 inflammasome activation may potentially contribute to the severity of COVID-19 and its aftermath. It is therefore possible that suppression of NLRP3 inflammasome activity may prove efficacious against both acute lung disease and chronic neurological after-effects. Because CA has been shown to not only act systemically but also to penetrate the blood-brain barrier and reach the brain parenchyma to exert neuroprotective effects, we discuss the evidence that CA or rosemary extracts containing CA may represent an effective countermeasure against both acute and chronic pathological events initiated by SARS-CoV-2 infection as well as other ch
Published: 2022

12. Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.

Author: Cabral-Miranda, Felipe, Cabral-Miranda, Felipe, Tamburini, Giovanni, Martinez, Gabriela, Ardiles, Alvaro, Medinas, Danilo, Gerakis, Yannis, Hung, Mei-Li, Vidal, René, Fuentealba, Matias, Miedema, Tim, Duran-Aniotz, Claudia, Diaz, Javier, Ibaceta-Gonzalez, Cristobal, Sabusap, Carleen, Bermedo-Garcia, Francisca, Mujica, Paula, Adamson, Stuart, Vitangcol, Kaitlyn, Huerta, Hernan, Zhang, Xu, Nakamura, Tomohiro, Sardi, Sergio, Kennedy, Brian, Henriquez, Juan, Cárdenas, J, Plate, Lars, Palacios, Adrian, Hetz, Claudio, Lipton, Stuart, Cabral-Miranda, Felipe, Cabral-Miranda, Felipe, Tamburini, Giovanni, Martinez, Gabriela, Ardiles, Alvaro, Medinas, Danilo, Gerakis, Yannis, Hung, Mei-Li, Vidal, René, Fuentealba, Matias, Miedema, Tim, Duran-Aniotz, Claudia, Diaz, Javier, Ibaceta-Gonzalez, Cristobal, Sabusap, Carleen, Bermedo-Garcia, Francisca, Mujica, Paula, Adamson, Stuart, Vitangcol, Kaitlyn, Huerta, Hernan, Zhang, Xu, Nakamura, Tomohiro, Sardi, Sergio, Kennedy, Brian, Henriquez, Juan, Cárdenas, J, Plate, Lars, Palacios, Adrian, Hetz, Claudio, and Lipton, Stuart
Abstract: Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.
Published: 2022

13. S-Nitrosylation of cathepsin B affects autophagic flux and accumulation of protein aggregates in neurodegenerative disorders.

Author: Kim, Ki-Ryeong, Kim, Ki-Ryeong, Cho, Eun-Jung, Eom, Jae-Won, Oh, Sang-Seok, Nakamura, Tomohiro, Oh, Chang-Ki, Kim, Yang-Hee, Lipton, Stuart, Kim, Ki-Ryeong, Kim, Ki-Ryeong, Cho, Eun-Jung, Eom, Jae-Won, Oh, Sang-Seok, Nakamura, Tomohiro, Oh, Chang-Ki, Kim, Yang-Hee, and Lipton, Stuart
Abstract: Protein S-nitrosylation is known to regulate enzymatic function. Here, we report that nitric oxide (NO)-related species can contribute to Alzheimers disease (AD) by S-nitrosylating the lysosomal protease cathepsin B (forming SNO-CTSB), thereby inhibiting CTSB activity. This posttranslational modification inhibited autophagic flux, increased autolysosomal vesicles, and led to accumulation of protein aggregates. CA-074Me, a CTSB chemical inhibitor, also inhibited autophagic flux and resulted in accumulation of protein aggregates similar to the effect of SNO-CTSB. Inhibition of CTSB activity also induced caspase-dependent neuronal apoptosis in mouse cerebrocortical cultures. To examine which cysteine residue(s) in CTSB are S-nitrosylated, we mutated candidate cysteines and found that three cysteines were susceptible to S-nitrosylation. Finally, we observed an increase in SNO-CTSB in both 5XFAD transgenic mouse and flash-frozen postmortem human AD brains. These results suggest that S-nitrosylation of CTSB inhibits enzymatic activity, blocks autophagic flux, and thus contributes to AD pathogenesis.
Published: 2022

14. NitroSynapsin ameliorates hypersynchronous neural network activity in Alzheimer hiPSC models.

Author: Ghatak, Swagata, Ghatak, Swagata, Dolatabadi, Nima, Gao, Richard, Wu, Yin, Scott, Henry, Trudler, Dorit, Sultan, Abdullah, Ambasudhan, Rajesh, Nakamura, Tomohiro, Masliah, Eliezer, Talantova, Maria, Voytek, Bradley, Lipton, Stuart A, Ghatak, Swagata, Ghatak, Swagata, Dolatabadi, Nima, Gao, Richard, Wu, Yin, Scott, Henry, Trudler, Dorit, Sultan, Abdullah, Ambasudhan, Rajesh, Nakamura, Tomohiro, Masliah, Eliezer, Talantova, Maria, Voytek, Bradley, and Lipton, Stuart A
Abstract: Beginning at early stages, human Alzheimer's disease (AD) brains manifest hyperexcitability, contributing to subsequent extensive synapse loss, which has been linked to cognitive dysfunction. No current therapy for AD is disease-modifying. Part of the problem with AD drug discovery is that transgenic mouse models have been poor predictors of potential human treatment. While it is undoubtedly important to test drugs in these animal models, additional evidence for drug efficacy in a human context might improve our chances of success. Accordingly, in order to test drugs in a human context, we have developed a platform of physiological assays using patch-clamp electrophysiology, calcium imaging, and multielectrode array (MEA) experiments on human (h)iPSC-derived 2D cortical neuronal cultures and 3D cerebral organoids. We compare hiPSCs bearing familial AD mutations vs. their wild-type (WT) isogenic controls in order to characterize the aberrant electrical activity in such a human context. Here, we show that these AD neuronal cultures and organoids manifest increased spontaneous action potentials, slow oscillatory events (~1 Hz), and hypersynchronous network activity. Importantly, the dual-allosteric NMDAR antagonist NitroSynapsin, but not the FDA-approved drug memantine, abrogated this hyperactivity. We propose a novel model of synaptic plasticity in which aberrant neural networks are rebalanced by NitroSynapsin. We propose that hiPSC models may be useful for screening drugs to treat hyperexcitability and related synaptic damage in AD.
Published: 2021

15. TCA cycle metabolic compromise due to an aberrant S-nitrosoproteome in HIV-associated neurocognitive disorder with methamphetamine use.

Author: Doulias, Paschalis-Thomas, Doulias, Paschalis-Thomas, Nakamura, Tomohiro, Scott, Henry, McKercher, Scott R, Sultan, Abdullah, Deal, Amanda, Albertolle, Matthew, Ischiropoulos, Harry, Lipton, Stuart A, Doulias, Paschalis-Thomas, Doulias, Paschalis-Thomas, Nakamura, Tomohiro, Scott, Henry, McKercher, Scott R, Sultan, Abdullah, Deal, Amanda, Albertolle, Matthew, Ischiropoulos, Harry, and Lipton, Stuart A
Abstract: In the brain, both HIV-1 and methamphetamine (meth) use result in increases in oxidative and nitrosative stress. This redox stress is thought to contribute to the pathogenesis of HIV-associated neurocognitive disorder (HAND) and further worsening cognitive activity in the setting of drug abuse. One consequence of such redox stress is aberrant protein S-nitrosylation, derived from nitric oxide, which may disrupt normal protein activity. Here, we report an improved, mass spectrometry-based technique to assess S-nitrosylated protein in human postmortem brains using selective enrichment of S-nitrosocysteine residues with an organomercury resin. The data show increasing S-nitrosylation of tricarboxylic acid (TCA) enzymes in the setting of HAND and HAND/meth use compared with HIV+ control brains without CNS pathology. The consequence is systematic inhibition of multiple TCA cycle enzymes, resulting in energy collapse that can contribute to the neuronal and synaptic damage observed in HAND and meth use.
Published: 2021

16. Protein Transnitrosylation Signaling Networks Contribute to Inflammaging and Neurodegenerative Disorders.

Author: Nakamura, Tomohiro, Nakamura, Tomohiro, Oh, Chang-Ki, Zhang, Xu, Tannenbaum, Steven R, Lipton, Stuart A, Nakamura, Tomohiro, Nakamura, Tomohiro, Oh, Chang-Ki, Zhang, Xu, Tannenbaum, Steven R, and Lipton, Stuart A
Abstract: Significance: Physiological concentrations of nitric oxide (NO•) and related reactive nitrogen species (RNS) mediate multiple signaling pathways in the nervous system. During inflammaging (chronic low-grade inflammation associated with aging) and in neurodegenerative diseases, excessive RNS contribute to synaptic and neuronal loss. "NO signaling" in both health and disease is largely mediated through protein S-nitrosylation (SNO), a redox-based posttranslational modification with "NO" (possibly in the form of nitrosonium cation [NO+]) reacting with cysteine thiol (or, more properly, thiolate anion [R-S-]). Recent Advances: Emerging evidence suggests that S-nitrosylation occurs predominantly via transnitros(yl)ation. Mechanistically, the reaction involves thiolate anion, as a nucleophile, performing a reversible nucleophilic attack on a nitroso nitrogen to form an SNO-protein adduct. Prior studies identified transnitrosylation reactions between glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-nuclear proteins, thioredoxin-caspase-3, and X-linked inhibitor of apoptosis (XIAP)-caspase-3. Recently, we discovered that enzymes previously thought to act in completely disparate biochemical pathways can transnitrosylate one another during inflammaging in an unexpected manner to mediate neurodegeneration. Accordingly, we reported a concerted tricomponent transnitrosylation network from Uch-L1-to-Cdk5-to-Drp1 that mediates synaptic damage in Alzheimer's disease. Critical Issues: Transnitrosylation represents a critical chemical mechanism for transduction of redox-mediated events to distinct subsets of proteins. Although thousands of thiol-containing proteins undergo S-nitrosylation, how transnitrosylation regulates a myriad of neuronal attributes is just now being uncovered. In this review, we highlight recent progress in the study of the chemical biology of transnitrosylation between proteins as a mechanism of disease. Future Directions: We discuss future areas of study of pr
Published: 2021

17. Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases.

Author: Trudler, Dorit, Trudler, Dorit, Ghatak, Swagata, Lipton, Stuart A, Trudler, Dorit, Trudler, Dorit, Ghatak, Swagata, and Lipton, Stuart A
Abstract: Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.
Published: 2021

18. Protein S-nitrosylation and oxidation contribute to protein misfolding in neurodegeneration.

Author: Nakamura, Tomohiro, Nakamura, Tomohiro, Oh, Chang-Ki, Zhang, Xu, Lipton, Stuart A, Nakamura, Tomohiro, Nakamura, Tomohiro, Oh, Chang-Ki, Zhang, Xu, and Lipton, Stuart A
Abstract: Neurodegenerative disorders like Alzheimer's disease and Parkinson's disease are characterized by progressive degeneration of synapses and neurons. Accumulation of misfolded/aggregated proteins represents a pathological hallmark of most neurodegenerative diseases, potentially contributing to synapse loss and neuronal damage. Emerging evidence suggests that misfolded proteins accumulate in the diseased brain at least in part as a consequence of excessively generated reactive oxygen species (ROS) and reactive nitrogen species (RNS). Mechanistically, not only disease-linked genetic mutations but also known risk factors for neurodegenerative diseases, such as aging and exposure to environmental toxins, can accelerate production of ROS/RNS, which contribute to protein misfolding - in many cases mimicking the effect of rare genetic mutations known to be linked to the disease. This review will focus on the role of RNS-dependent post-translational modifications, such as S-nitrosylation and tyrosine nitration, in protein misfolding and aggregation. Specifically, we will discuss molecular mechanisms whereby RNS disrupt the activity of the cellular protein quality control machinery, including molecular chaperones, autophagy/lysosomal pathways, and the ubiquitin-proteasome system (UPS). Because chronic accumulation of misfolded proteins can trigger mitochondrial dysfunction, synaptic damage, and neuronal demise, further characterization of RNS-mediated protein misfolding may establish these molecular events as therapeutic targets for intervention in neurodegenerative diseases.
Published: 2021

19. S-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD.

Author: Pirie, Elaine, Pirie, Elaine, Oh, Chang-Ki, Zhang, Xu, Han, Xuemei, Cieplak, Piotr, Scott, Henry R, Deal, Amanda K, Ghatak, Swagata, Martinez, Fernando J, Yeo, Gene W, Yates, John R, Nakamura, Tomohiro, Lipton, Stuart A, Pirie, Elaine, Pirie, Elaine, Oh, Chang-Ki, Zhang, Xu, Han, Xuemei, Cieplak, Piotr, Scott, Henry R, Deal, Amanda K, Ghatak, Swagata, Martinez, Fernando J, Yeo, Gene W, Yates, John R, Nakamura, Tomohiro, and Lipton, Stuart A
Abstract: Rare genetic mutations result in aggregation and spreading of cognate proteins in neurodegenerative disorders; however, in the absence of mutation (i.e., in the vast majority of "sporadic" cases), mechanisms for protein misfolding/aggregation remain largely unknown. Here, we show environmentally induced nitrosative stress triggers protein aggregation and cell-to-cell spread. In patient brains with amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), aggregation of the RNA-binding protein TDP-43 constitutes a major component of aberrant cytoplasmic inclusions. We identify a pathological signaling cascade whereby reactive nitrogen species cause S-nitrosylation of TDP-43 (forming SNO-TDP-43) to facilitate disulfide linkage and consequent TDP-43 aggregation. Similar pathological SNO-TDP-43 levels occur in postmortem human FTD/ALS brains and in cell-based models, including human-induced pluripotent stem cell (hiPSC)-derived neurons. Aggregated TDP-43 triggers additional nitrosative stress, representing positive feed forward leading to further SNO-TDP-43 formation and disulfide-linked oligomerization/aggregation. Critically, we show that these redox reactions facilitate cell spreading in vivo and interfere with the TDP-43 RNA-binding activity, affecting SNMT1 and phospho-(p)CREB levels, thus contributing to neuronal damage in ALS/FTD disorders.
Published: 2021

20. Noncanonical transnitrosylation network contributes to synapse loss in Alzheimer's disease.

Author: Nakamura, Tomohiro, Nakamura, Tomohiro, Oh, Chang-Ki, Liao, Lujian, Zhang, Xu, Lopez, Kevin M, Gibbs, Daniel, Deal, Amanda K, Scott, Henry R, Spencer, Brian, Masliah, Eliezer, Rissman, Robert A, Yates, John R, Lipton, Stuart A, Nakamura, Tomohiro, Nakamura, Tomohiro, Oh, Chang-Ki, Liao, Lujian, Zhang, Xu, Lopez, Kevin M, Gibbs, Daniel, Deal, Amanda K, Scott, Henry R, Spencer, Brian, Masliah, Eliezer, Rissman, Robert A, Yates, John R, and Lipton, Stuart A
Abstract: Here we describe mechanistically distinct enzymes (a kinase, a guanosine triphosphatase, and a ubiquitin protein hydrolase) that function in disparate biochemical pathways and can also act in concert to mediate a series of redox reactions. Each enzyme manifests a second, noncanonical function-transnitrosylation-that triggers a pathological biochemical cascade in mouse models and in humans with Alzheimer's disease (AD). The resulting series of transnitrosylation reactions contributes to synapse loss, the major pathological correlate to cognitive decline in AD. We conclude that enzymes with distinct primary reaction mechanisms can form a completely separate network for aberrant transnitrosylation. This network operates in the postreproductive period, so natural selection against such abnormal activity may be decreased.
Published: 2021

21. Protein Transnitrosylation Signaling Networks Contribute to Inflammaging and Neurodegenerative Disorders

Author: Massachusetts Institute of Technology. Department of Biological Engineering, Nakamura, Tomohiro, Oh, Chang-ki, Zhang, Xu, Tannenbaum, Steven R, Lipton, Stuart A, Massachusetts Institute of Technology. Department of Biological Engineering, Nakamura, Tomohiro, Oh, Chang-ki, Zhang, Xu, Tannenbaum, Steven R, and Lipton, Stuart A
Abstract: Significance: Physiological concentrations of nitric oxide (NO•) and related reactive nitrogen species (RNS) mediate multiple signaling pathways in the nervous system. During inflammaging (chronic low-grade inflammation associated with aging) and in neurodegenerative diseases, excessive RNS contribute to synaptic and neuronal loss. "NO signaling" in both health and disease is largely mediated through protein S-nitrosylation (SNO), a redox-based posttranslational modification with "NO" (possibly in the form of nitrosonium cation [NO+]) reacting with cysteine thiol (or, more properly, thiolate anion [R-S-]). Recent Advances: Emerging evidence suggests that S-nitrosylation occurs predominantly via transnitros(yl)ation. Mechanistically, the reaction involves thiolate anion, as a nucleophile, performing a reversible nucleophilic attack on a nitroso nitrogen to form an SNO-protein adduct. Prior studies identified transnitrosylation reactions between glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-nuclear proteins, thioredoxin-caspase-3, and X-linked inhibitor of apoptosis (XIAP)-caspase-3. Recently, we discovered that enzymes previously thought to act in completely disparate biochemical pathways can transnitrosylate one another during inflammaging in an unexpected manner to mediate neurodegeneration. Accordingly, we reported a concerted tricomponent transnitrosylation network from Uch-L1-to-Cdk5-to-Drp1 that mediates synaptic damage in Alzheimer's disease. Critical Issues: Transnitrosylation represents a critical chemical mechanism for transduction of redox-mediated events to distinct subsets of proteins. Although thousands of thiol-containing proteins undergo S-nitrosylation, how transnitrosylation regulates a myriad of neuronal attributes is just now being uncovered. In this review, we highlight recent progress in the study of the chemical biology of transnitrosylation between proteins as a mechanism of disease. Future Directions: We discuss future areas of study of pr
Published: 2021

22. Nitric Oxide-Dependent Protein Post-Translational Modifications Impair Mitochondrial Function and Metabolism to Contribute to Neurodegenerative Diseases.

Author: Nakamura, Tomohiro, Nakamura, Tomohiro, Lipton, Stuart A, Nakamura, Tomohiro, Nakamura, Tomohiro, and Lipton, Stuart A
Abstract: Significance: Most brains affected by neurodegenerative diseases manifest mitochondrial dysfunction as well as elevated production of reactive oxygen species and reactive nitrogen species (RNS), contributing to synapse loss and neuronal injury. Recent Advances: Excessive production of RNS triggers nitric oxide (NO)-mediated post-translational modifications of proteins, such as S-nitrosylation of cysteine residues and nitration of tyrosine residues. Proteins thus affected impair mitochondrial metabolism, mitochondrial dynamics, and mitophagy in the nervous system. Critical Issues: Identification and better characterization of underlying molecular mechanisms for NO-mediated mitochondrial dysfunction will provide important insights into the pathogenesis of neurodegenerative disorders. In this review, we highlight recent discoveries concerning S-nitrosylation of the tricarboxylic acid cycle enzymes, mitochondrial fission GTPase dynamin-related protein 1, and mitophagy-related proteins Parkin and phosphatase and tensin homolog-induced putative kinase protein 1. We delineate signaling cascades affected by pathologically S-nitrosylated proteins that diminish mitochondrial function in neurodegenerative diseases. Future Directions: Further elucidation of the pathological events resulting from aberrant S-nitrosothiol or nitrotyrosine formation may lead to new therapeutic approaches to ameliorate neurodegenerative disorders.
Published: 2020

23. Novel Direct Conversion of Microglia to Neurons.

Author: Trudler, Dorit, Trudler, Dorit, Lipton, Stuart A, Trudler, Dorit, Trudler, Dorit, and Lipton, Stuart A
Abstract: Direct cell reprogramming, the process by which a somatic cell is converted to another cell type, can potentially circumvent epigenetic changes and proliferative stages resulting from de-differentiation. Recently, Matsuda et al. (Pioneer factor NeuroD1 rearranges transcriptional and epigenetic profiles to execute microglia-neuron conversion; Neuronin in press) demonstrated that expression of transcription factor NeuroD1 can convert mouse microglia to neurons, both in vitro and in vivo.
Published: 2019

24. NitroSynapsin for the treatment of neurological manifestations of tuberous sclerosis complex in a rodent model.

Author: Okamoto, Shu-Ichi, Okamoto, Shu-Ichi, Prikhodko, Olga, Pina-Crespo, Juan, Adame, Anthony, McKercher, Scott R, Brill, Laurence M, Nakanishi, Nobuki, Oh, Chang-Ki, Nakamura, Tomohiro, Masliah, Eliezer, Lipton, Stuart A, Okamoto, Shu-Ichi, Okamoto, Shu-Ichi, Prikhodko, Olga, Pina-Crespo, Juan, Adame, Anthony, McKercher, Scott R, Brill, Laurence M, Nakanishi, Nobuki, Oh, Chang-Ki, Nakamura, Tomohiro, Masliah, Eliezer, and Lipton, Stuart A
Abstract: Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by heterozygous mutations in the TSC1 or TSC2 gene. TSC is often associated with neurological, cognitive, and behavioral deficits. TSC patients also express co-morbidity with anxiety and mood disorders. The mechanism of pathogenesis in TSC is not entirely clear, but TSC-related neurological symptoms are accompanied by excessive glutamatergic activity and altered synaptic spine structures. To address whether extrasynaptic (e)NMDA-type glutamate receptor (NMDAR) antagonists, as opposed to antagonists that block physiological phasic synaptic activity, can ameliorate the synaptic and behavioral features of this disease, we utilized the Tsc2+/- mouse model of TSC to measure biochemical, electrophysiological, histological, and behavioral parameters in the mice. We found that antagonists that preferentially block tonic activity as found at eNMDARs, particularly the newer drug NitroSynapsin, provide biological and statistically significant improvement in Tsc2+/- phenotypes. Accompanying this improvement was correction of activity in the p38 MAPK-TSC-Rheb-mTORC1-S6K1 pathway. Deficits in hippocampal long-term potentiation (LTP), histological loss of synapses, and behavioral fear conditioning in Tsc2+/- mice were all improved after treatment with NitroSynapsin. Taken together, these results suggest that amelioration of excessive excitation, by limiting aberrant eNMDAR activity, may represent a novel treatment approach for TSC.
Published: 2019

25. Mechanisms of hyperexcitability in Alzheimer's disease hiPSC-derived neurons and cerebral organoids vs isogenic controls.

Author: Ghatak, Swagata, Ghatak, Swagata, Dolatabadi, Nima, Trudler, Dorit, Zhang, XiaoTong, Wu, Yin, Mohata, Madhav, Ambasudhan, Rajesh, Talantova, Maria, Lipton, Stuart A, Ghatak, Swagata, Ghatak, Swagata, Dolatabadi, Nima, Trudler, Dorit, Zhang, XiaoTong, Wu, Yin, Mohata, Madhav, Ambasudhan, Rajesh, Talantova, Maria, and Lipton, Stuart A
Abstract: Human Alzheimer's disease (AD) brains and transgenic AD mouse models manifest hyperexcitability. This aberrant electrical activity is caused by synaptic dysfunction that represents the major pathophysiological correlate of cognitive decline. However, the underlying mechanism for this excessive excitability remains incompletely understood. To investigate the basis for the hyperactivity, we performed electrophysiological and immunofluorescence studies on hiPSC-derived cerebrocortical neuronal cultures and cerebral organoids bearing AD-related mutations in presenilin-1 or amyloid precursor protein vs. isogenic gene corrected controls. In the AD hiPSC-derived neurons/organoids, we found increased excitatory bursting activity, which could be explained in part by a decrease in neurite length. AD hiPSC-derived neurons also displayed increased sodium current density and increased excitatory and decreased inhibitory synaptic activity. Our findings establish hiPSC-derived AD neuronal cultures and organoids as a relevant model of early AD pathophysiology and provide mechanistic insight into the observed hyperexcitability.
Published: 2019

26. Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases.

Author: Connolly, Niamh MC, Connolly, Niamh MC, Theurey, Pierre, Adam-Vizi, Vera, Bazan, Nicolas G, Bernardi, Paolo, Bolaños, Juan P, Culmsee, Carsten, Dawson, Valina L, Deshmukh, Mohanish, Duchen, Michael R, Düssmann, Heiko, Fiskum, Gary, Galindo, Maria F, Hardingham, Giles E, Hardwick, J Marie, Jekabsons, Mika B, Jonas, Elizabeth A, Jordán, Joaquin, Lipton, Stuart A, Manfredi, Giovanni, Mattson, Mark P, McLaughlin, BethAnn, Methner, Axel, Murphy, Anne N, Murphy, Michael P, Nicholls, David G, Polster, Brian M, Pozzan, Tullio, Rizzuto, Rosario, Satrústegui, Jorgina, Slack, Ruth S, Swanson, Raymond A, Swerdlow, Russell H, Will, Yvonne, Ying, Zheng, Joselin, Alvin, Gioran, Anna, Moreira Pinho, Catarina, Watters, Orla, Salvucci, Manuela, Llorente-Folch, Irene, Park, David S, Bano, Daniele, Ankarcrona, Maria, Pizzo, Paola, Prehn, Jochen HM, Connolly, Niamh MC, Connolly, Niamh MC, Theurey, Pierre, Adam-Vizi, Vera, Bazan, Nicolas G, Bernardi, Paolo, Bolaños, Juan P, Culmsee, Carsten, Dawson, Valina L, Deshmukh, Mohanish, Duchen, Michael R, Düssmann, Heiko, Fiskum, Gary, Galindo, Maria F, Hardingham, Giles E, Hardwick, J Marie, Jekabsons, Mika B, Jonas, Elizabeth A, Jordán, Joaquin, Lipton, Stuart A, Manfredi, Giovanni, Mattson, Mark P, McLaughlin, BethAnn, Methner, Axel, Murphy, Anne N, Murphy, Michael P, Nicholls, David G, Polster, Brian M, Pozzan, Tullio, Rizzuto, Rosario, Satrústegui, Jorgina, Slack, Ruth S, Swanson, Raymond A, Swerdlow, Russell H, Will, Yvonne, Ying, Zheng, Joselin, Alvin, Gioran, Anna, Moreira Pinho, Catarina, Watters, Orla, Salvucci, Manuela, Llorente-Folch, Irene, Park, David S, Bano, Daniele, Ankarcrona, Maria, Pizzo, Paola, and Prehn, Jochen HM
Abstract: Neurodegenerative diseases are a spectrum of chronic, debilitating disorders characterised by the progressive degeneration and death of neurons. Mitochondrial dysfunction has been implicated in most neurodegenerative diseases, but in many instances it is unclear whether such dysfunction is a cause or an effect of the underlying pathology, and whether it represents a viable therapeutic target. It is therefore imperative to utilise and optimise cellular models and experimental techniques appropriate to determine the contribution of mitochondrial dysfunction to neurodegenerative disease phenotypes. In this consensus article, we collate details on and discuss pitfalls of existing experimental approaches to assess mitochondrial function in in vitro cellular models of neurodegenerative diseases, including specific protocols for the measurement of oxygen consumption rate in primary neuron cultures, and single-neuron, time-lapse fluorescence imaging of the mitochondrial membrane potential and mitochondrial NAD(P)H. As part of the Cellular Bioenergetics of Neurodegenerative Diseases (CeBioND) consortium ( www.cebiond.org ), we are performing cross-disease analyses to identify common and distinct molecular mechanisms involved in mitochondrial bioenergetic dysfunction in cellular models of Alzheimer's, Parkinson's, and Huntington's diseases. Here we provide detailed guidelines and protocols as standardised across the five collaborating laboratories of the CeBioND consortium, with additional contributions from other experts in the field.
Published: 2018

27. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Author: Galluzzi, Lorenzo, Galluzzi, Lorenzo, Vitale, Ilio, Aaronson, Stuart A, Abrams, John M, Adam, Dieter, Agostinis, Patrizia, Alnemri, Emad S, Altucci, Lucia, Amelio, Ivano, Andrews, David W, Annicchiarico-Petruzzelli, Margherita, Antonov, Alexey V, Arama, Eli, Baehrecke, Eric H, Barlev, Nickolai A, Bazan, Nicolas G, Bernassola, Francesca, Bertrand, Mathieu JM, Bianchi, Katiuscia, Blagosklonny, Mikhail V, Blomgren, Klas, Borner, Christoph, Boya, Patricia, Brenner, Catherine, Campanella, Michelangelo, Candi, Eleonora, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K-M, Chandel, Navdeep S, Cheng, Emily H, Chipuk, Jerry E, Cidlowski, John A, Ciechanover, Aaron, Cohen, Gerald M, Conrad, Marcus, Cubillos-Ruiz, Juan R, Czabotar, Peter E, D'Angiolella, Vincenzo, Dawson, Ted M, Dawson, Valina L, De Laurenzi, Vincenzo, De Maria, Ruggero, Debatin, Klaus-Michael, DeBerardinis, Ralph J, Deshmukh, Mohanish, Di Daniele, Nicola, Di Virgilio, Francesco, Dixit, Vishva M, Dixon, Scott J, Duckett, Colin S, Dynlacht, Brian D, El-Deiry, Wafik S, Elrod, John W, Fimia, Gian Maria, Fulda, Simone, García-Sáez, Ana J, Garg, Abhishek D, Garrido, Carmen, Gavathiotis, Evripidis, Golstein, Pierre, Gottlieb, Eyal, Green, Douglas R, Greene, Lloyd A, Gronemeyer, Hinrich, Gross, Atan, Hajnoczky, Gyorgy, Hardwick, J Marie, Harris, Isaac S, Hengartner, Michael O, Hetz, Claudio, Ichijo, Hidenori, Jäättelä, Marja, Joseph, Bertrand, Jost, Philipp J, Juin, Philippe P, Kaiser, William J, Karin, Michael, Kaufmann, Thomas, Kepp, Oliver, Kimchi, Adi, Kitsis, Richard N, Klionsky, Daniel J, Knight, Richard A, Kumar, Sharad, Lee, Sam W, Lemasters, John J, Levine, Beth, Linkermann, Andreas, Lipton, Stuart A, Lockshin, Richard A, López-Otín, Carlos, Lowe, Scott W, Luedde, Tom, Lugli, Enrico, MacFarlane, Marion, Madeo, Frank, Malewicz, Michal, Malorni, Walter, Manic, Gwenola, Galluzzi, Lorenzo, Galluzzi, Lorenzo, Vitale, Ilio, Aaronson, Stuart A, Abrams, John M, Adam, Dieter, Agostinis, Patrizia, Alnemri, Emad S, Altucci, Lucia, Amelio, Ivano, Andrews, David W, Annicchiarico-Petruzzelli, Margherita, Antonov, Alexey V, Arama, Eli, Baehrecke, Eric H, Barlev, Nickolai A, Bazan, Nicolas G, Bernassola, Francesca, Bertrand, Mathieu JM, Bianchi, Katiuscia, Blagosklonny, Mikhail V, Blomgren, Klas, Borner, Christoph, Boya, Patricia, Brenner, Catherine, Campanella, Michelangelo, Candi, Eleonora, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K-M, Chandel, Navdeep S, Cheng, Emily H, Chipuk, Jerry E, Cidlowski, John A, Ciechanover, Aaron, Cohen, Gerald M, Conrad, Marcus, Cubillos-Ruiz, Juan R, Czabotar, Peter E, D'Angiolella, Vincenzo, Dawson, Ted M, Dawson, Valina L, De Laurenzi, Vincenzo, De Maria, Ruggero, Debatin, Klaus-Michael, DeBerardinis, Ralph J, Deshmukh, Mohanish, Di Daniele, Nicola, Di Virgilio, Francesco, Dixit, Vishva M, Dixon, Scott J, Duckett, Colin S, Dynlacht, Brian D, El-Deiry, Wafik S, Elrod, John W, Fimia, Gian Maria, Fulda, Simone, García-Sáez, Ana J, Garg, Abhishek D, Garrido, Carmen, Gavathiotis, Evripidis, Golstein, Pierre, Gottlieb, Eyal, Green, Douglas R, Greene, Lloyd A, Gronemeyer, Hinrich, Gross, Atan, Hajnoczky, Gyorgy, Hardwick, J Marie, Harris, Isaac S, Hengartner, Michael O, Hetz, Claudio, Ichijo, Hidenori, Jäättelä, Marja, Joseph, Bertrand, Jost, Philipp J, Juin, Philippe P, Kaiser, William J, Karin, Michael, Kaufmann, Thomas, Kepp, Oliver, Kimchi, Adi, Kitsis, Richard N, Klionsky, Daniel J, Knight, Richard A, Kumar, Sharad, Lee, Sam W, Lemasters, John J, Levine, Beth, Linkermann, Andreas, Lipton, Stuart A, Lockshin, Richard A, López-Otín, Carlos, Lowe, Scott W, Luedde, Tom, Lugli, Enrico, MacFarlane, Marion, Madeo, Frank, Malewicz, Michal, Malorni, Walter, and Manic, Gwenola
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
Published: 2018

28. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Author: Galluzzi, Lorenzo, Vitale, Ilio, Aaronson, Stuart A., Abrams, John M., Adam, Dieter, Agostinis, Patrizia, Alnemri, Emad S., Altucci, Lucia, Amelio, Ivano, Andrews, David W., Annicchiarico-Petruzzelli, Margherita, Antonov, Alexey V., Arama, Eli, Baehrecke, Eric H., Barlev, Nickolai A., Bazan, Nicolas G., Bernassola, Francesca, Bertrand, Mathieu J. M., Bianchi, Katiuscia, Blagosklonny, Mikhail V., Blomgren, Klas, Borner, Christoph, Boya, Patricia, Brenner, Catherine, Campanella, Michelangelo, Candi, Eleonora, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K. -M., Chandel, Navdeep S., Cheng, Emily H., Chipuk, Jerry E., Cidlowski, John A., Ciechanover, Aaron, Cohen, Gerald M., Conrad, Marcus, Cubillos-Ruiz, Juan R., Czabotar, Peter E., D'Angiolella, Vincenzo, Dawson, Ted M., Dawson, Valina L., De laurenzi, Vincenzo, De Maria, Ruggero, Debatin, Klaus-Michael, DeBerardinis, Ralph J., Deshmukh, Mohanish, Di Daniele, Nicola, Di Virgilio, Francesco, Dixit, Vishva M., Dixon, Scott J., Duckett, Colin S., Dynlacht, Brian D., El-Deiry, Wafik S., Elrod, John W., Fimia, Gian Maria, Fulda, Simone, Garcia-Saez, Ana J., Garg, Abhishek D., Garrido, Carmen, Gavathiotis, Evripidis, Golstein, Pierre, Gottlieb, Eyal, Green, Douglas R., Greene, Lloyd A., Gronemeyer, Hinrich, Gross, Atan, Hajnoczky, Gyorgy, Hardwick, J. Marie, Harris, Isaac S., Hengartner, Michael O., Hetz, Claudio, Ichijo, Hidenori, Jaattela, Marja, Joseph, Bertrand, Jost, Philipp J., Juin, Philippe P., Kaiser, William J., Karin, Michael, Kaufmann, Thomas, Kepp, Oliver, Kimchi, Adi, Kitsis, Richard N., Klionsky, Daniel J., Knight, Richard A., Kumar, Sharad, Lee, Sam W., Lemasters, John J., Levine, Beth, Linkermann, Andreas, Lipton, Stuart A., Lockshin, Richard A., Lopez-Otin, Carlos, Lowe, Scott W., Luedde, Tom, Lugli, Enrico, MacFarlane, Marion, Madeo, Frank, Malewicz, Michal, Malorni, Walter, Manic, Gwenola, Marine, Jean-Christophe, Martin, Seamus J., Martinou, Jean-Claude, Medema, Jan Paul, Mehlen, Patrick, Meier, Pascal, Melino, Sonia, Miao, Edward A., Molkentin, Jeffery D., Moll, Ute M., Munoz-Pinedo, Cristina, Nagata, Shigekazu, Nunez, Gabriel, Oberst, Andrew, Oren, Moshe, Overholtzer, Michael, Pagano, Michele, Panaretakis, Theocharis, Pasparakis, Manolis, Penninger, Josef M., Pereira, David M., Pervaiz, Shazib, Peter, Marcus E., Piacentini, Mauro, Pinton, Paolo, Prehn, Jochen H. M., Puthalakath, Hamsa, Rabinovich, Gabriel A., Rehm, Markus, Rizzuto, Rosario, Rodrigues, Cecilia M. P., Rubinsztein, David C., Rudel, Thomas, Ryan, Kevin M., Sayan, Emre, Scorrano, Luca, Shao, Feng, Shi, Yufang, Silke, John, Simon, Hans-Uwe, Sistigu, Antonella, Stockwell, Brent R., Strasser, Andreas, Szabadkai, Gyorgy, Tait, Stephen W. G., Tang, Daolin, Tavernarakis, Nektarios, Thorburn, Andrew, Tsujimoto, Yoshihide, Turk, Boris, Vanden Berghe, Tom, Vandenabeele, Peter, Heiden, Matthew G. Vander, Villunger, Andreas, Virgin, Herbert W., Vousden, Karen H., Vucic, Domagoj, Wagner, Erwin F., Walczak, Henning, Wallach, David, Wang, Ying, Wells, James A., Wood, Will, Yuan, Junying, Zakeri, Zahra, Zhivotovsky, Boris, Zitvogel, Laurence, Melino, Gerry, Kroemer, Guido, Galluzzi, Lorenzo, Vitale, Ilio, Aaronson, Stuart A., Abrams, John M., Adam, Dieter, Agostinis, Patrizia, Alnemri, Emad S., Altucci, Lucia, Amelio, Ivano, Andrews, David W., Annicchiarico-Petruzzelli, Margherita, Antonov, Alexey V., Arama, Eli, Baehrecke, Eric H., Barlev, Nickolai A., Bazan, Nicolas G., Bernassola, Francesca, Bertrand, Mathieu J. M., Bianchi, Katiuscia, Blagosklonny, Mikhail V., Blomgren, Klas, Borner, Christoph, Boya, Patricia, Brenner, Catherine, Campanella, Michelangelo, Candi, Eleonora, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K. -M., Chandel, Navdeep S., Cheng, Emily H., Chipuk, Jerry E., Cidlowski, John A., Ciechanover, Aaron, Cohen, Gerald M., Conrad, Marcus, Cubillos-Ruiz, Juan R., Czabotar, Peter E., D'Angiolella, Vincenzo, Dawson, Ted M., Dawson, Valina L., De laurenzi, Vincenzo, De Maria, Ruggero, Debatin, Klaus-Michael, DeBerardinis, Ralph J., Deshmukh, Mohanish, Di Daniele, Nicola, Di Virgilio, Francesco, Dixit, Vishva M., Dixon, Scott J., Duckett, Colin S., Dynlacht, Brian D., El-Deiry, Wafik S., Elrod, John W., Fimia, Gian Maria, Fulda, Simone, Garcia-Saez, Ana J., Garg, Abhishek D., Garrido, Carmen, Gavathiotis, Evripidis, Golstein, Pierre, Gottlieb, Eyal, Green, Douglas R., Greene, Lloyd A., Gronemeyer, Hinrich, Gross, Atan, Hajnoczky, Gyorgy, Hardwick, J. Marie, Harris, Isaac S., Hengartner, Michael O., Hetz, Claudio, Ichijo, Hidenori, Jaattela, Marja, Joseph, Bertrand, Jost, Philipp J., Juin, Philippe P., Kaiser, William J., Karin, Michael, Kaufmann, Thomas, Kepp, Oliver, Kimchi, Adi, Kitsis, Richard N., Klionsky, Daniel J., Knight, Richard A., Kumar, Sharad, Lee, Sam W., Lemasters, John J., Levine, Beth, Linkermann, Andreas, Lipton, Stuart A., Lockshin, Richard A., Lopez-Otin, Carlos, Lowe, Scott W., Luedde, Tom, Lugli, Enrico, MacFarlane, Marion, Madeo, Frank, Malewicz, Michal, Malorni, Walter, Manic, Gwenola, Marine, Jean-Christophe, Martin, Seamus J., Martinou, Jean-Claude, Medema, Jan Paul, Mehlen, Patrick, Meier, Pascal, Melino, Sonia, Miao, Edward A., Molkentin, Jeffery D., Moll, Ute M., Munoz-Pinedo, Cristina, Nagata, Shigekazu, Nunez, Gabriel, Oberst, Andrew, Oren, Moshe, Overholtzer, Michael, Pagano, Michele, Panaretakis, Theocharis, Pasparakis, Manolis, Penninger, Josef M., Pereira, David M., Pervaiz, Shazib, Peter, Marcus E., Piacentini, Mauro, Pinton, Paolo, Prehn, Jochen H. M., Puthalakath, Hamsa, Rabinovich, Gabriel A., Rehm, Markus, Rizzuto, Rosario, Rodrigues, Cecilia M. P., Rubinsztein, David C., Rudel, Thomas, Ryan, Kevin M., Sayan, Emre, Scorrano, Luca, Shao, Feng, Shi, Yufang, Silke, John, Simon, Hans-Uwe, Sistigu, Antonella, Stockwell, Brent R., Strasser, Andreas, Szabadkai, Gyorgy, Tait, Stephen W. G., Tang, Daolin, Tavernarakis, Nektarios, Thorburn, Andrew, Tsujimoto, Yoshihide, Turk, Boris, Vanden Berghe, Tom, Vandenabeele, Peter, Heiden, Matthew G. Vander, Villunger, Andreas, Virgin, Herbert W., Vousden, Karen H., Vucic, Domagoj, Wagner, Erwin F., Walczak, Henning, Wallach, David, Wang, Ying, Wells, James A., Wood, Will, Yuan, Junying, Zakeri, Zahra, Zhivotovsky, Boris, Zitvogel, Laurence, Melino, Gerry, and Kroemer, Guido
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
Published: 2018

29. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Author: Galluzzi, Lorenzo, Galluzzi, Lorenzo, Vitale, Ilio, Aaronson, Stuart A, Abrams, John M, Adam, Dieter, Agostinis, Patrizia, Alnemri, Emad S, Altucci, Lucia, Amelio, Ivano, Andrews, David W, Annicchiarico-Petruzzelli, Margherita, Antonov, Alexey V, Arama, Eli, Baehrecke, Eric H, Barlev, Nickolai A, Bazan, Nicolas G, Bernassola, Francesca, Bertrand, Mathieu JM, Bianchi, Katiuscia, Blagosklonny, Mikhail V, Blomgren, Klas, Borner, Christoph, Boya, Patricia, Brenner, Catherine, Campanella, Michelangelo, Candi, Eleonora, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K-M, Chandel, Navdeep S, Cheng, Emily H, Chipuk, Jerry E, Cidlowski, John A, Ciechanover, Aaron, Cohen, Gerald M, Conrad, Marcus, Cubillos-Ruiz, Juan R, Czabotar, Peter E, D'Angiolella, Vincenzo, Dawson, Ted M, Dawson, Valina L, De Laurenzi, Vincenzo, De Maria, Ruggero, Debatin, Klaus-Michael, DeBerardinis, Ralph J, Deshmukh, Mohanish, Di Daniele, Nicola, Di Virgilio, Francesco, Dixit, Vishva M, Dixon, Scott J, Duckett, Colin S, Dynlacht, Brian D, El-Deiry, Wafik S, Elrod, John W, Fimia, Gian Maria, Fulda, Simone, García-Sáez, Ana J, Garg, Abhishek D, Garrido, Carmen, Gavathiotis, Evripidis, Golstein, Pierre, Gottlieb, Eyal, Green, Douglas R, Greene, Lloyd A, Gronemeyer, Hinrich, Gross, Atan, Hajnoczky, Gyorgy, Hardwick, J Marie, Harris, Isaac S, Hengartner, Michael O, Hetz, Claudio, Ichijo, Hidenori, Jäättelä, Marja, Joseph, Bertrand, Jost, Philipp J, Juin, Philippe P, Kaiser, William J, Karin, Michael, Kaufmann, Thomas, Kepp, Oliver, Kimchi, Adi, Kitsis, Richard N, Klionsky, Daniel J, Knight, Richard A, Kumar, Sharad, Lee, Sam W, Lemasters, John J, Levine, Beth, Linkermann, Andreas, Lipton, Stuart A, Lockshin, Richard A, López-Otín, Carlos, Lowe, Scott W, Luedde, Tom, Lugli, Enrico, MacFarlane, Marion, Madeo, Frank, Malewicz, Michal, Malorni, Walter, Manic, Gwenola, Galluzzi, Lorenzo, Galluzzi, Lorenzo, Vitale, Ilio, Aaronson, Stuart A, Abrams, John M, Adam, Dieter, Agostinis, Patrizia, Alnemri, Emad S, Altucci, Lucia, Amelio, Ivano, Andrews, David W, Annicchiarico-Petruzzelli, Margherita, Antonov, Alexey V, Arama, Eli, Baehrecke, Eric H, Barlev, Nickolai A, Bazan, Nicolas G, Bernassola, Francesca, Bertrand, Mathieu JM, Bianchi, Katiuscia, Blagosklonny, Mikhail V, Blomgren, Klas, Borner, Christoph, Boya, Patricia, Brenner, Catherine, Campanella, Michelangelo, Candi, Eleonora, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K-M, Chandel, Navdeep S, Cheng, Emily H, Chipuk, Jerry E, Cidlowski, John A, Ciechanover, Aaron, Cohen, Gerald M, Conrad, Marcus, Cubillos-Ruiz, Juan R, Czabotar, Peter E, D'Angiolella, Vincenzo, Dawson, Ted M, Dawson, Valina L, De Laurenzi, Vincenzo, De Maria, Ruggero, Debatin, Klaus-Michael, DeBerardinis, Ralph J, Deshmukh, Mohanish, Di Daniele, Nicola, Di Virgilio, Francesco, Dixit, Vishva M, Dixon, Scott J, Duckett, Colin S, Dynlacht, Brian D, El-Deiry, Wafik S, Elrod, John W, Fimia, Gian Maria, Fulda, Simone, García-Sáez, Ana J, Garg, Abhishek D, Garrido, Carmen, Gavathiotis, Evripidis, Golstein, Pierre, Gottlieb, Eyal, Green, Douglas R, Greene, Lloyd A, Gronemeyer, Hinrich, Gross, Atan, Hajnoczky, Gyorgy, Hardwick, J Marie, Harris, Isaac S, Hengartner, Michael O, Hetz, Claudio, Ichijo, Hidenori, Jäättelä, Marja, Joseph, Bertrand, Jost, Philipp J, Juin, Philippe P, Kaiser, William J, Karin, Michael, Kaufmann, Thomas, Kepp, Oliver, Kimchi, Adi, Kitsis, Richard N, Klionsky, Daniel J, Knight, Richard A, Kumar, Sharad, Lee, Sam W, Lemasters, John J, Levine, Beth, Linkermann, Andreas, Lipton, Stuart A, Lockshin, Richard A, López-Otín, Carlos, Lowe, Scott W, Luedde, Tom, Lugli, Enrico, MacFarlane, Marion, Madeo, Frank, Malewicz, Michal, Malorni, Walter, and Manic, Gwenola
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
Published: 2018

30. Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases.

Author: Connolly, Niamh MC, Connolly, Niamh MC, Theurey, Pierre, Adam-Vizi, Vera, Bazan, Nicolas G, Bernardi, Paolo, Bolaños, Juan P, Culmsee, Carsten, Dawson, Valina L, Deshmukh, Mohanish, Duchen, Michael R, Düssmann, Heiko, Fiskum, Gary, Galindo, Maria F, Hardingham, Giles E, Hardwick, J Marie, Jekabsons, Mika B, Jonas, Elizabeth A, Jordán, Joaquin, Lipton, Stuart A, Manfredi, Giovanni, Mattson, Mark P, McLaughlin, BethAnn, Methner, Axel, Murphy, Anne N, Murphy, Michael P, Nicholls, David G, Polster, Brian M, Pozzan, Tullio, Rizzuto, Rosario, Satrústegui, Jorgina, Slack, Ruth S, Swanson, Raymond A, Swerdlow, Russell H, Will, Yvonne, Ying, Zheng, Joselin, Alvin, Gioran, Anna, Moreira Pinho, Catarina, Watters, Orla, Salvucci, Manuela, Llorente-Folch, Irene, Park, David S, Bano, Daniele, Ankarcrona, Maria, Pizzo, Paola, Prehn, Jochen HM, Connolly, Niamh MC, Connolly, Niamh MC, Theurey, Pierre, Adam-Vizi, Vera, Bazan, Nicolas G, Bernardi, Paolo, Bolaños, Juan P, Culmsee, Carsten, Dawson, Valina L, Deshmukh, Mohanish, Duchen, Michael R, Düssmann, Heiko, Fiskum, Gary, Galindo, Maria F, Hardingham, Giles E, Hardwick, J Marie, Jekabsons, Mika B, Jonas, Elizabeth A, Jordán, Joaquin, Lipton, Stuart A, Manfredi, Giovanni, Mattson, Mark P, McLaughlin, BethAnn, Methner, Axel, Murphy, Anne N, Murphy, Michael P, Nicholls, David G, Polster, Brian M, Pozzan, Tullio, Rizzuto, Rosario, Satrústegui, Jorgina, Slack, Ruth S, Swanson, Raymond A, Swerdlow, Russell H, Will, Yvonne, Ying, Zheng, Joselin, Alvin, Gioran, Anna, Moreira Pinho, Catarina, Watters, Orla, Salvucci, Manuela, Llorente-Folch, Irene, Park, David S, Bano, Daniele, Ankarcrona, Maria, Pizzo, Paola, and Prehn, Jochen HM
Abstract: Neurodegenerative diseases are a spectrum of chronic, debilitating disorders characterised by the progressive degeneration and death of neurons. Mitochondrial dysfunction has been implicated in most neurodegenerative diseases, but in many instances it is unclear whether such dysfunction is a cause or an effect of the underlying pathology, and whether it represents a viable therapeutic target. It is therefore imperative to utilise and optimise cellular models and experimental techniques appropriate to determine the contribution of mitochondrial dysfunction to neurodegenerative disease phenotypes. In this consensus article, we collate details on and discuss pitfalls of existing experimental approaches to assess mitochondrial function in in vitro cellular models of neurodegenerative diseases, including specific protocols for the measurement of oxygen consumption rate in primary neuron cultures, and single-neuron, time-lapse fluorescence imaging of the mitochondrial membrane potential and mitochondrial NAD(P)H. As part of the Cellular Bioenergetics of Neurodegenerative Diseases (CeBioND) consortium ( www.cebiond.org ), we are performing cross-disease analyses to identify common and distinct molecular mechanisms involved in mitochondrial bioenergetic dysfunction in cellular models of Alzheimer's, Parkinson's, and Huntington's diseases. Here we provide detailed guidelines and protocols as standardised across the five collaborating laboratories of the CeBioND consortium, with additional contributions from other experts in the field.
Published: 2018

31. Publisher Correction: Identification of a peptide recognizing cerebrovascular changes in mouse models of Alzheimer's disease.

Author: Mann, Aman P, Mann, Aman P, Scodeller, Pablo, Hussain, Sazid, Braun, Gary B, Mölder, Tarmo, Toome, Kadri, Ambasudhan, Rajesh, Teesalu, Tambet, Lipton, Stuart A, Ruoslahti, Erkki, Mann, Aman P, Mann, Aman P, Scodeller, Pablo, Hussain, Sazid, Braun, Gary B, Mölder, Tarmo, Toome, Kadri, Ambasudhan, Rajesh, Teesalu, Tambet, Lipton, Stuart A, and Ruoslahti, Erkki
Abstract: The original version of the Supplementary Information associated with this Article inadvertently omitted Supplementary Table 1. The HTML has now been updated to include a corrected version of the Supplementary Information.
Published: 2018

32. The mouse as a model for neuropsychiatric drug development.

Author: Howe, James R, Howe, James R, Bear, Mark F, Golshani, Peyman, Klann, Eric, Lipton, Stuart A, Mucke, Lennart, Sahin, Mustafa, Silva, Alcino J, Howe, James R, Howe, James R, Bear, Mark F, Golshani, Peyman, Klann, Eric, Lipton, Stuart A, Mucke, Lennart, Sahin, Mustafa, and Silva, Alcino J
Abstract: Much has been written about the validity of mice as a preclinical model for brain disorders. Critics cite numerous examples of apparently effective treatments in mouse models that failed in human clinical trials, raising the possibility that the two species' neurobiological differences could explain the high translational failure rate in psychiatry and neurology (neuropsychiatry). However, every stage of translation is plagued by complex problems unrelated to neurobiological conservation. Therefore, although these case studies are intriguing, they cannot alone determine whether these differences observed account for translation failures. Our analysis of the literature indicates that most neuropsychiatric treatments used in humans are at least partially effective in mouse models, suggesting that neurobiological differences are unlikely to be the main cause of neuropsychiatric translation failures.
Published: 2018

33. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Author: Galluzzi, Lorenzo, Vitale, Ilio, Aaronson, Stuart A., Abrams, John M., Adam, Dieter, Agostinis, Patrizia, Alnemri, Emad S., Altucci, Lucia, Amelio, Ivano, Andrews, David W., Annicchiarico-Petruzzelli, Margherita, Antonov, Alexey V., Arama, Eli, Baehrecke, Eric H., Barlev, Nickolai A., Bazan, Nicolas G., Bernassola, Francesca, Bertrand, Mathieu J. M., Bianchi, Katiuscia, Blagosklonny, Mikhail V., Blomgren, Klas, Borner, Christoph, Boya, Patricia, Brenner, Catherine, Campanella, Michelangelo, Candi, Eleonora, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K. -M., Chandel, Navdeep S., Cheng, Emily H., Chipuk, Jerry E., Cidlowski, John A., Ciechanover, Aaron, Cohen, Gerald M., Conrad, Marcus, Cubillos-Ruiz, Juan R., Czabotar, Peter E., D'Angiolella, Vincenzo, Dawson, Ted M., Dawson, Valina L., De laurenzi, Vincenzo, De Maria, Ruggero, Debatin, Klaus-Michael, DeBerardinis, Ralph J., Deshmukh, Mohanish, Di Daniele, Nicola, Di Virgilio, Francesco, Dixit, Vishva M., Dixon, Scott J., Duckett, Colin S., Dynlacht, Brian D., El-Deiry, Wafik S., Elrod, John W., Fimia, Gian Maria, Fulda, Simone, Garcia-Saez, Ana J., Garg, Abhishek D., Garrido, Carmen, Gavathiotis, Evripidis, Golstein, Pierre, Gottlieb, Eyal, Green, Douglas R., Greene, Lloyd A., Gronemeyer, Hinrich, Gross, Atan, Hajnoczky, Gyorgy, Hardwick, J. Marie, Harris, Isaac S., Hengartner, Michael O., Hetz, Claudio, Ichijo, Hidenori, Jaattela, Marja, Joseph, Bertrand, Jost, Philipp J., Juin, Philippe P., Kaiser, William J., Karin, Michael, Kaufmann, Thomas, Kepp, Oliver, Kimchi, Adi, Kitsis, Richard N., Klionsky, Daniel J., Knight, Richard A., Kumar, Sharad, Lee, Sam W., Lemasters, John J., Levine, Beth, Linkermann, Andreas, Lipton, Stuart A., Lockshin, Richard A., Lopez-Otin, Carlos, Lowe, Scott W., Luedde, Tom, Lugli, Enrico, MacFarlane, Marion, Madeo, Frank, Malewicz, Michal, Malorni, Walter, Manic, Gwenola, Marine, Jean-Christophe, Martin, Seamus J., Martinou, Jean-Claude, Medema, Jan Paul, Mehlen, Patrick, Meier, Pascal, Melino, Sonia, Miao, Edward A., Molkentin, Jeffery D., Moll, Ute M., Munoz-Pinedo, Cristina, Nagata, Shigekazu, Nunez, Gabriel, Oberst, Andrew, Oren, Moshe, Overholtzer, Michael, Pagano, Michele, Panaretakis, Theocharis, Pasparakis, Manolis, Penninger, Josef M., Pereira, David M., Pervaiz, Shazib, Peter, Marcus E., Piacentini, Mauro, Pinton, Paolo, Prehn, Jochen H. M., Puthalakath, Hamsa, Rabinovich, Gabriel A., Rehm, Markus, Rizzuto, Rosario, Rodrigues, Cecilia M. P., Rubinsztein, David C., Rudel, Thomas, Ryan, Kevin M., Sayan, Emre, Scorrano, Luca, Shao, Feng, Shi, Yufang, Silke, John, Simon, Hans-Uwe, Sistigu, Antonella, Stockwell, Brent R., Strasser, Andreas, Szabadkai, Gyorgy, Tait, Stephen W. G., Tang, Daolin, Tavernarakis, Nektarios, Thorburn, Andrew, Tsujimoto, Yoshihide, Turk, Boris, Vanden Berghe, Tom, Vandenabeele, Peter, Heiden, Matthew G. Vander, Villunger, Andreas, Virgin, Herbert W., Vousden, Karen H., Vucic, Domagoj, Wagner, Erwin F., Walczak, Henning, Wallach, David, Wang, Ying, Wells, James A., Wood, Will, Yuan, Junying, Zakeri, Zahra, Zhivotovsky, Boris, Zitvogel, Laurence, Melino, Gerry, Kroemer, Guido, Galluzzi, Lorenzo, Vitale, Ilio, Aaronson, Stuart A., Abrams, John M., Adam, Dieter, Agostinis, Patrizia, Alnemri, Emad S., Altucci, Lucia, Amelio, Ivano, Andrews, David W., Annicchiarico-Petruzzelli, Margherita, Antonov, Alexey V., Arama, Eli, Baehrecke, Eric H., Barlev, Nickolai A., Bazan, Nicolas G., Bernassola, Francesca, Bertrand, Mathieu J. M., Bianchi, Katiuscia, Blagosklonny, Mikhail V., Blomgren, Klas, Borner, Christoph, Boya, Patricia, Brenner, Catherine, Campanella, Michelangelo, Candi, Eleonora, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K. -M., Chandel, Navdeep S., Cheng, Emily H., Chipuk, Jerry E., Cidlowski, John A., Ciechanover, Aaron, Cohen, Gerald M., Conrad, Marcus, Cubillos-Ruiz, Juan R., Czabotar, Peter E., D'Angiolella, Vincenzo, Dawson, Ted M., Dawson, Valina L., De laurenzi, Vincenzo, De Maria, Ruggero, Debatin, Klaus-Michael, DeBerardinis, Ralph J., Deshmukh, Mohanish, Di Daniele, Nicola, Di Virgilio, Francesco, Dixit, Vishva M., Dixon, Scott J., Duckett, Colin S., Dynlacht, Brian D., El-Deiry, Wafik S., Elrod, John W., Fimia, Gian Maria, Fulda, Simone, Garcia-Saez, Ana J., Garg, Abhishek D., Garrido, Carmen, Gavathiotis, Evripidis, Golstein, Pierre, Gottlieb, Eyal, Green, Douglas R., Greene, Lloyd A., Gronemeyer, Hinrich, Gross, Atan, Hajnoczky, Gyorgy, Hardwick, J. Marie, Harris, Isaac S., Hengartner, Michael O., Hetz, Claudio, Ichijo, Hidenori, Jaattela, Marja, Joseph, Bertrand, Jost, Philipp J., Juin, Philippe P., Kaiser, William J., Karin, Michael, Kaufmann, Thomas, Kepp, Oliver, Kimchi, Adi, Kitsis, Richard N., Klionsky, Daniel J., Knight, Richard A., Kumar, Sharad, Lee, Sam W., Lemasters, John J., Levine, Beth, Linkermann, Andreas, Lipton, Stuart A., Lockshin, Richard A., Lopez-Otin, Carlos, Lowe, Scott W., Luedde, Tom, Lugli, Enrico, MacFarlane, Marion, Madeo, Frank, Malewicz, Michal, Malorni, Walter, Manic, Gwenola, Marine, Jean-Christophe, Martin, Seamus J., Martinou, Jean-Claude, Medema, Jan Paul, Mehlen, Patrick, Meier, Pascal, Melino, Sonia, Miao, Edward A., Molkentin, Jeffery D., Moll, Ute M., Munoz-Pinedo, Cristina, Nagata, Shigekazu, Nunez, Gabriel, Oberst, Andrew, Oren, Moshe, Overholtzer, Michael, Pagano, Michele, Panaretakis, Theocharis, Pasparakis, Manolis, Penninger, Josef M., Pereira, David M., Pervaiz, Shazib, Peter, Marcus E., Piacentini, Mauro, Pinton, Paolo, Prehn, Jochen H. M., Puthalakath, Hamsa, Rabinovich, Gabriel A., Rehm, Markus, Rizzuto, Rosario, Rodrigues, Cecilia M. P., Rubinsztein, David C., Rudel, Thomas, Ryan, Kevin M., Sayan, Emre, Scorrano, Luca, Shao, Feng, Shi, Yufang, Silke, John, Simon, Hans-Uwe, Sistigu, Antonella, Stockwell, Brent R., Strasser, Andreas, Szabadkai, Gyorgy, Tait, Stephen W. G., Tang, Daolin, Tavernarakis, Nektarios, Thorburn, Andrew, Tsujimoto, Yoshihide, Turk, Boris, Vanden Berghe, Tom, Vandenabeele, Peter, Heiden, Matthew G. Vander, Villunger, Andreas, Virgin, Herbert W., Vousden, Karen H., Vucic, Domagoj, Wagner, Erwin F., Walczak, Henning, Wallach, David, Wang, Ying, Wells, James A., Wood, Will, Yuan, Junying, Zakeri, Zahra, Zhivotovsky, Boris, Zitvogel, Laurence, Melino, Gerry, and Kroemer, Guido
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
Published: 2018

34. Gelatinase activity imaged by activatable cell-penetrating peptides in cell-based and in vivo models of stroke.

Author: Chen, Shanyan, Chen, Shanyan, Cui, Jiankun, Jiang, Tao, Olson, Emilia S, Cai, Quan-Yu, Yang, Ming, Wu, Wei, Guthrie, James M, Robertson, JD, Lipton, Stuart A, Ma, Lixin, Tsien, Roger Y, Gu, Zezong, Chen, Shanyan, Chen, Shanyan, Cui, Jiankun, Jiang, Tao, Olson, Emilia S, Cai, Quan-Yu, Yang, Ming, Wu, Wei, Guthrie, James M, Robertson, JD, Lipton, Stuart A, Ma, Lixin, Tsien, Roger Y, and Gu, Zezong
Abstract: Matrix metalloproteinases (MMPs), particularly gelatinases (MMP-2/-9), are involved in neurovascular impairment after stroke. Detection of gelatinase activity in vivo can provide insight into blood-brain barrier disruption, hemorrhage, and nerve cell injury or death. We applied gelatinase-activatable cell-penetrating peptides (ACPP) with a cleavable l-amino acid linker to examine gelatinase activity in primary neurons in culture and ischemic mouse brain in vivo We found uptake of Cy5-conjugated ACPP (ACPP-Cy5) due to gelatinase activation both in cultured neurons exposed to n-methyl-d-aspartate and in mice after cerebral ischemia. Fluorescence intensity was significantly reduced when cells or mice were treated with MMP inhibitors or when a cleavage-resistant ACPP-Cy5 was substituted. We also applied an ACPP dendrimer (ACPPD) conjugated with multiple Cy5 and/or gadolinium moieties for fluorescence and magnetic resonance imaging (MRI) in intact animals. Fluorescence analysis showed that ACPPD was detected in sub-femtomole range in ischemic tissues. Moreover, MRI and inductively coupled plasma mass spectrometry revealed that ACPPD produced quantitative measures of gelatinase activity in the ischemic region. The resulting spatial pattern of gelatinase activity and neurodegeneration were very similar. We conclude that ACPPs are capable of tracing spatiotemporal gelatinase activity in vivo, and will therefore be useful in elucidating mechanisms of gelatinase-mediated neurodegeneration after stroke.
Published: 2017

35. NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism.

Author: Tu, Shichun, Tu, Shichun, Akhtar, Mohd Waseem, Escorihuela, Rosa Maria, Amador-Arjona, Alejandro, Swarup, Vivek, Parker, James, Zaremba, Jeffrey D, Holland, Timothy, Bansal, Neha, Holohan, Daniel R, Lopez, Kevin, Ryan, Scott D, Chan, Shing Fai, Yan, Li, Zhang, Xiaofei, Huang, Xiayu, Sultan, Abdullah, McKercher, Scott R, Ambasudhan, Rajesh, Xu, Huaxi, Wang, Yuqiang, Geschwind, Daniel H, Roberts, Amanda J, Terskikh, Alexey V, Rissman, Robert A, Masliah, Eliezer, Lipton, Stuart A, Nakanishi, Nobuki, Tu, Shichun, Tu, Shichun, Akhtar, Mohd Waseem, Escorihuela, Rosa Maria, Amador-Arjona, Alejandro, Swarup, Vivek, Parker, James, Zaremba, Jeffrey D, Holland, Timothy, Bansal, Neha, Holohan, Daniel R, Lopez, Kevin, Ryan, Scott D, Chan, Shing Fai, Yan, Li, Zhang, Xiaofei, Huang, Xiayu, Sultan, Abdullah, McKercher, Scott R, Ambasudhan, Rajesh, Xu, Huaxi, Wang, Yuqiang, Geschwind, Daniel H, Roberts, Amanda J, Terskikh, Alexey V, Rissman, Robert A, Masliah, Eliezer, Lipton, Stuart A, and Nakanishi, Nobuki
Abstract: Transcription factor MEF2C regulates multiple genes linked to autism spectrum disorder (ASD), and human MEF2C haploinsufficiency results in ASD, intellectual disability, and epilepsy. However, molecular mechanisms underlying MEF2C haploinsufficiency syndrome remain poorly understood. Here we report that Mef2c +/-(Mef2c-het) mice exhibit behavioral deficits resembling those of human patients. Gene expression analyses on brains from these mice show changes in genes associated with neurogenesis, synapse formation, and neuronal cell death. Accordingly, Mef2c-het mice exhibit decreased neurogenesis, enhanced neuronal apoptosis, and an increased ratio of excitatory to inhibitory (E/I) neurotransmission. Importantly, neurobehavioral deficits, E/I imbalance, and histological damage are all ameliorated by treatment with NitroSynapsin, a new dual-action compound related to the FDA-approved drug memantine, representing an uncompetitive/fast off-rate antagonist of NMDA-type glutamate receptors. These results suggest that MEF2C haploinsufficiency leads to abnormal brain development, E/I imbalance, and neurobehavioral dysfunction, which may be mitigated by pharmacological intervention.
Published: 2017

36. Gelatinase activity imaged by activatable cell-penetrating peptides in cell-based and in vivo models of stroke.

Author: Chen, Shanyan, Chen, Shanyan, Cui, Jiankun, Jiang, Tao, Olson, Emilia S, Cai, Quan-Yu, Yang, Ming, Wu, Wei, Guthrie, James M, Robertson, JD, Lipton, Stuart A, Ma, Lixin, Tsien, Roger Y, Gu, Zezong, Chen, Shanyan, Chen, Shanyan, Cui, Jiankun, Jiang, Tao, Olson, Emilia S, Cai, Quan-Yu, Yang, Ming, Wu, Wei, Guthrie, James M, Robertson, JD, Lipton, Stuart A, Ma, Lixin, Tsien, Roger Y, and Gu, Zezong
Abstract: Matrix metalloproteinases (MMPs), particularly gelatinases (MMP-2/-9), are involved in neurovascular impairment after stroke. Detection of gelatinase activity in vivo can provide insight into blood-brain barrier disruption, hemorrhage, and nerve cell injury or death. We applied gelatinase-activatable cell-penetrating peptides (ACPP) with a cleavable l-amino acid linker to examine gelatinase activity in primary neurons in culture and ischemic mouse brain in vivo We found uptake of Cy5-conjugated ACPP (ACPP-Cy5) due to gelatinase activation both in cultured neurons exposed to n-methyl-d-aspartate and in mice after cerebral ischemia. Fluorescence intensity was significantly reduced when cells or mice were treated with MMP inhibitors or when a cleavage-resistant ACPP-Cy5 was substituted. We also applied an ACPP dendrimer (ACPPD) conjugated with multiple Cy5 and/or gadolinium moieties for fluorescence and magnetic resonance imaging (MRI) in intact animals. Fluorescence analysis showed that ACPPD was detected in sub-femtomole range in ischemic tissues. Moreover, MRI and inductively coupled plasma mass spectrometry revealed that ACPPD produced quantitative measures of gelatinase activity in the ischemic region. The resulting spatial pattern of gelatinase activity and neurodegeneration were very similar. We conclude that ACPPs are capable of tracing spatiotemporal gelatinase activity in vivo, and will therefore be useful in elucidating mechanisms of gelatinase-mediated neurodegeneration after stroke.
Published: 2017

37. NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism.

Author: Tu, Shichun, Tu, Shichun, Akhtar, Mohd Waseem, Escorihuela, Rosa Maria, Amador-Arjona, Alejandro, Swarup, Vivek, Parker, James, Zaremba, Jeffrey D, Holland, Timothy, Bansal, Neha, Holohan, Daniel R, Lopez, Kevin, Ryan, Scott D, Chan, Shing Fai, Yan, Li, Zhang, Xiaofei, Huang, Xiayu, Sultan, Abdullah, McKercher, Scott R, Ambasudhan, Rajesh, Xu, Huaxi, Wang, Yuqiang, Geschwind, Daniel H, Roberts, Amanda J, Terskikh, Alexey V, Rissman, Robert A, Masliah, Eliezer, Lipton, Stuart A, Nakanishi, Nobuki, Tu, Shichun, Tu, Shichun, Akhtar, Mohd Waseem, Escorihuela, Rosa Maria, Amador-Arjona, Alejandro, Swarup, Vivek, Parker, James, Zaremba, Jeffrey D, Holland, Timothy, Bansal, Neha, Holohan, Daniel R, Lopez, Kevin, Ryan, Scott D, Chan, Shing Fai, Yan, Li, Zhang, Xiaofei, Huang, Xiayu, Sultan, Abdullah, McKercher, Scott R, Ambasudhan, Rajesh, Xu, Huaxi, Wang, Yuqiang, Geschwind, Daniel H, Roberts, Amanda J, Terskikh, Alexey V, Rissman, Robert A, Masliah, Eliezer, Lipton, Stuart A, and Nakanishi, Nobuki
Abstract: Transcription factor MEF2C regulates multiple genes linked to autism spectrum disorder (ASD), and human MEF2C haploinsufficiency results in ASD, intellectual disability, and epilepsy. However, molecular mechanisms underlying MEF2C haploinsufficiency syndrome remain poorly understood. Here we report that Mef2c +/-(Mef2c-het) mice exhibit behavioral deficits resembling those of human patients. Gene expression analyses on brains from these mice show changes in genes associated with neurogenesis, synapse formation, and neuronal cell death. Accordingly, Mef2c-het mice exhibit decreased neurogenesis, enhanced neuronal apoptosis, and an increased ratio of excitatory to inhibitory (E/I) neurotransmission. Importantly, neurobehavioral deficits, E/I imbalance, and histological damage are all ameliorated by treatment with NitroSynapsin, a new dual-action compound related to the FDA-approved drug memantine, representing an uncompetitive/fast off-rate antagonist of NMDA-type glutamate receptors. These results suggest that MEF2C haploinsufficiency leads to abnormal brain development, E/I imbalance, and neurobehavioral dysfunction, which may be mitigated by pharmacological intervention.
Published: 2017

38. Identification of a peptide recognizing cerebrovascular changes in mouse models of Alzheimer's disease.

Author: Mann, Aman P, Mann, Aman P, Scodeller, Pablo, Hussain, Sazid, Braun, Gary B, Mölder, Tarmo, Toome, Kadri, Ambasudhan, Rajesh, Teesalu, Tambet, Lipton, Stuart A, Ruoslahti, Erkki, Mann, Aman P, Mann, Aman P, Scodeller, Pablo, Hussain, Sazid, Braun, Gary B, Mölder, Tarmo, Toome, Kadri, Ambasudhan, Rajesh, Teesalu, Tambet, Lipton, Stuart A, and Ruoslahti, Erkki
Abstract: Cerebrovascular changes occur in Alzheimer's disease (AD). Using in vivo phage display, we searched for molecular markers of the neurovascular unit, including endothelial cells and astrocytes, in mouse models of AD. We identified a cyclic peptide, CDAGRKQKC (DAG), that accumulates in the hippocampus of hAPP-J20 mice at different ages. Intravenously injected DAG peptide homes to neurovascular unit endothelial cells and to reactive astrocytes in mouse models of AD. We identified connective tissue growth factor (CTGF), a matricellular protein that is highly expressed in the brain of individuals with AD and in mouse models, as the target of the DAG peptide. We also showed that exogenously delivered DAG homes to the brain in mouse models of glioblastoma, traumatic brain injury, and Parkinson's disease. DAG may potentially be used as a tool to enhance delivery of therapeutics and imaging agents to sites of vascular changes and astrogliosis in diseases associated with neuroinflammation.
Published: 2017

39. 'SNO'-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders.

Author: Nakamura, Tomohiro, Nakamura, Tomohiro, Lipton, Stuart A, Nakamura, Tomohiro, Nakamura, Tomohiro, and Lipton, Stuart A
Abstract: The prevalence of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), is currently a major public health concern due to the lack of efficient disease-modifying therapeutic options. Recent evidence suggests that mitochondrial dysfunction and nitrosative/oxidative stress are key common mediators of pathogenesis. In this review, we highlight molecular mechanisms linking NO-dependent post-translational modifications, such as cysteine S-nitrosylation and tyrosine nitration, to abnormal mitochondrial metabolism. We further discuss the hypothesis that pathological levels of NO compromise brain energy metabolism via aberrant S-nitrosylation of key enzymes in the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, contributing to neurodegenerative conditions. A better understanding of these pathophysiological events may provide a potential pathway for designing novel therapeutics to ameliorate neurodegenerative disorders.
Published: 2017

40. Recent advances in understanding NRF2 as a druggable target: development of pro-electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate.

Author: Satoh, Takumi, Satoh, Takumi, Lipton, Stuart, Satoh, Takumi, Satoh, Takumi, and Lipton, Stuart
Abstract: Dimethyl fumarate (DMF) is an electrophilic compound previously called BG-12 and marketed under the name Tecfidera ®. It was approved in 2013 by the US Food and Drug Administration and the European Medicines Agency for the treatment of relapsing multiple sclerosis. One mechanism of action of DMF is stimulation of the nuclear factor erythroid 2-related factor 2 (NRF2) transcriptional pathway that induces anti-oxidant and anti-inflammatory phase II enzymes to prevent chronic neurodegeneration. However, electrophiles such as DMF also produce severe systemic side effects, in part due to non-specific S-alkylation of cysteine thiols and resulting depletion of glutathione. This mini-review presents the present status and future strategy for NRF2 activators designed to avoid these side effects. Two modes of chemical reaction leading to NRF2 activation are considered here. The first mode is S-alkylation (covalent reaction) of thiols in Kelch-like ECH-associated protein 1 (KEAP1), which interacts with NRF2. The second mechanism involves non-covalent pharmacological inhibition of protein-protein interactions, in particular domain-specific interaction between NRF2 and KEAP1 or other repressor proteins involved in this transcriptional pathway. There have been significant advances in drug development using both of these mechanisms that can potentially avoid the systemic side effects of electrophilic compounds. In the first case concerning covalent reaction with KEAP1, monomethyl fumarate and monoethyl fumarate appear to represent safer derivatives of DMF. In a second approach, pro-electrophilic drugs, such as carnosic acid from the herb Rosmarinus officinalis, can be used as a safe pro-drug of an electrophilic compound. Concerning non-covalent activation of NRF2, drugs are being developed that interfere with the direct interaction of KEAP1-NRF2 or inhibit BTB domain and CNC homolog 1 (BACH1), which is a transcriptional repressor of the promoter where NRF2 binds.
Published: 2017

41. Gelatinase activity imaged by activatable cell-penetrating peptides in cell-based and in vivo models of stroke.

Author: Chen, Shanyan, Chen, Shanyan, Cui, Jiankun, Jiang, Tao, Olson, Emilia, Cai, Quan-Yu, Yang, Ming, Wu, Wei, Guthrie, James, Robertson, J, Gu, Zezong, Ma, Lixin, Tsien, Roger, Lipton, Stuart, Chen, Shanyan, Chen, Shanyan, Cui, Jiankun, Jiang, Tao, Olson, Emilia, Cai, Quan-Yu, Yang, Ming, Wu, Wei, Guthrie, James, Robertson, J, Gu, Zezong, Ma, Lixin, Tsien, Roger, and Lipton, Stuart
Abstract: Matrix metalloproteinases (MMPs), particularly gelatinases (MMP-2/-9), are involved in neurovascular impairment after stroke. Detection of gelatinase activity in vivo can provide insight into blood-brain barrier disruption, hemorrhage, and nerve cell injury or death. We applied gelatinase-activatable cell-penetrating peptides (ACPP) with a cleavable l-amino acid linker to examine gelatinase activity in primary neurons in culture and ischemic mouse brain in vivo We found uptake of Cy5-conjugated ACPP (ACPP-Cy5) due to gelatinase activation both in cultured neurons exposed to n-methyl-d-aspartate and in mice after cerebral ischemia. Fluorescence intensity was significantly reduced when cells or mice were treated with MMP inhibitors or when a cleavage-resistant ACPP-Cy5 was substituted. We also applied an ACPP dendrimer (ACPPD) conjugated with multiple Cy5 and/or gadolinium moieties for fluorescence and magnetic resonance imaging (MRI) in intact animals. Fluorescence analysis showed that ACPPD was detected in sub-femtomole range in ischemic tissues. Moreover, MRI and inductively coupled plasma mass spectrometry revealed that ACPPD produced quantitative measures of gelatinase activity in the ischemic region. The resulting spatial pattern of gelatinase activity and neurodegeneration were very similar. We conclude that ACPPs are capable of tracing spatiotemporal gelatinase activity in vivo, and will therefore be useful in elucidating mechanisms of gelatinase-mediated neurodegeneration after stroke.
Published: 2017

42. MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress.

Author: Nagar, Saumya, Nagar, Saumya, Noveral, Sarah M, Trudler, Dorit, Lopez, Kevin M, McKercher, Scott R, Han, Xuemei, Yates, John R, Piña-Crespo, Juan C, Nakanishi, Nobuki, Satoh, Takumi, Okamoto, Shu-Ichi, Lipton, Stuart A, Nagar, Saumya, Nagar, Saumya, Noveral, Sarah M, Trudler, Dorit, Lopez, Kevin M, McKercher, Scott R, Han, Xuemei, Yates, John R, Piña-Crespo, Juan C, Nakanishi, Nobuki, Satoh, Takumi, Okamoto, Shu-Ichi, and Lipton, Stuart A
Abstract: Gaining mechanistic insight into interaction between causative factors of complex multifactorial diseases involving photoreceptor damage might aid in devising effective therapies. Oxidative stress is one of the potential unifying mechanisms for interplay between genetic and environmental factors that contribute to photoreceptor pathology. Interestingly, the transcription factor myocyte enhancer factor 2d (MEF2D) is known to be important in photoreceptor survival, as knockout of this transcription factor results in loss of photoreceptors in mice. Here, using a mild light-induced retinal degeneration model, we show that the diminished MEF2D transcriptional activity in Mef2d+/- retina is further reduced under photostimulation-induced oxidative stress. Reactive oxygen species cause an aberrant redox modification on MEF2D, consequently inhibiting transcription of its downstream target, nuclear factor (erythroid-derived 2)-like 2 (NRF2). NRF2 is a master regulator of phase II antiinflammatory and antioxidant gene expression. In the Mef2d heterozygous mouse retina, NRF2 is not up-regulated to a normal degree in the face of light-induced oxidative stress, contributing to accelerated photoreceptor cell death. Furthermore, to combat this injury, we found that activation of the endogenous NRF2 pathway using proelectrophilic drugs rescues photoreceptors from photo-induced oxidative stress and may therefore represent a viable treatment for oxidative stress-induced photoreceptor degeneration, which is thought to contribute to some forms of retinitis pigmentosa and age-related macular degeneration.
Published: 2017

43. Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases

Author: European Commission, Canadian Institutes of Health Research, Federal Ministry of Education and Research (Germany), Science Foundation Ireland, Ministero dell'Istruzione, dell'Università e della Ricerca, Swedish Research Council, Connolly, Niamh M. C. [0000-0002-6005-1307], Bernardi, Paolo [0000-0001-9187-3736], Culmsee, Carsten [0000-0002-5121-5015], Dawson, Valina L. [0000-0002-2915-3970], Duchen, Michael R. [0000-0003-2548-4294], Methner, Axel [0000-0002-8774-0057], Polster, Brian M. [0000-0002-8705-3628], Park, David S. [0000-0002-4490-3784], Connolly, Niamh M. C., Theurey, Pierre, Adam-Vizi, Vera, Bazan, Nicolas G., Bernardi, Paolo, Bolaños, Juan P., Culmsee, Carsten, Dawson, Valina L., Deshmukh, Mohanish, Duchen, Michael R., Düssmann, Heiko, Fiskum, Gary, Galindo, María F., Hardingham, Giles E., Hardwick, J. Marie, Jekabsons, Mika B., Jonas, Elizabeth A., Jordán, Joaquín, Lipton, Stuart A., Manfredi, Giovanni, Mattson, Mark P., McLaughlin, BethAnn, Methner, Axel, Murphy, Anne N., Murphy, Michael P., Nicholls, David G., Polster, Brian M., Pozzan, Tulio, Rizzuto, Rosario, Satrústegui, Jorgina, Slack, Ruth S., Swanson, Raymond A., Swerdlow, Russell H., Will, Yvonne, Ying, Zheng, Joselin, Alvin, Gioran, Anna, Moreira Pinho, Catarina, Watters, Orla, Salvucci, Manuela, Llorente-Folch, Irene, Park, David S., Bano, Daniele, Ankarcrona, Maria, Pizzo, Paola, Prehn, Jochen H. M., European Commission, Canadian Institutes of Health Research, Federal Ministry of Education and Research (Germany), Science Foundation Ireland, Ministero dell'Istruzione, dell'Università e della Ricerca, Swedish Research Council, Connolly, Niamh M. C. [0000-0002-6005-1307], Bernardi, Paolo [0000-0001-9187-3736], Culmsee, Carsten [0000-0002-5121-5015], Dawson, Valina L. [0000-0002-2915-3970], Duchen, Michael R. [0000-0003-2548-4294], Methner, Axel [0000-0002-8774-0057], Polster, Brian M. [0000-0002-8705-3628], Park, David S. [0000-0002-4490-3784], Connolly, Niamh M. C., Theurey, Pierre, Adam-Vizi, Vera, Bazan, Nicolas G., Bernardi, Paolo, Bolaños, Juan P., Culmsee, Carsten, Dawson, Valina L., Deshmukh, Mohanish, Duchen, Michael R., Düssmann, Heiko, Fiskum, Gary, Galindo, María F., Hardingham, Giles E., Hardwick, J. Marie, Jekabsons, Mika B., Jonas, Elizabeth A., Jordán, Joaquín, Lipton, Stuart A., Manfredi, Giovanni, Mattson, Mark P., McLaughlin, BethAnn, Methner, Axel, Murphy, Anne N., Murphy, Michael P., Nicholls, David G., Polster, Brian M., Pozzan, Tulio, Rizzuto, Rosario, Satrústegui, Jorgina, Slack, Ruth S., Swanson, Raymond A., Swerdlow, Russell H., Will, Yvonne, Ying, Zheng, Joselin, Alvin, Gioran, Anna, Moreira Pinho, Catarina, Watters, Orla, Salvucci, Manuela, Llorente-Folch, Irene, Park, David S., Bano, Daniele, Ankarcrona, Maria, Pizzo, Paola, and Prehn, Jochen H. M.
Abstract: Neurodegenerative diseases are a spectrum of chronic, debilitating disorders characterised by the progressive degeneration and death of neurons. Mitochondrial dysfunction has been implicated in most neurodegenerative diseases, but in many instances it is unclear whether such dysfunction is a cause or an effect of the underlying pathology, and whether it represents a viable therapeutic target. It is therefore imperative to utilise and optimise cellular models and experimental techniques appropriate to determine the contribution of mitochondrial dysfunction to neurodegenerative disease phenotypes. In this consensus article, we collate details on and discuss pitfalls of existing experimental approaches to assess mitochondrial function in in vitro cellular models of neurodegenerative diseases, including specific protocols for the measurement of oxygen consumption rate in primary neuron cultures, and single-neuron, time-lapse fluorescence imaging of the mitochondrial membrane potential and mitochondrial NAD(P)H. As part of the Cellular Bioenergetics of Neurodegenerative Diseases (CeBioND) consortium (www.cebiond.org), we are performing cross-disease analyses to identify common and distinct molecular mechanisms involved in mitochondrial bioenergetic dysfunction in cellular models of Alzheimer’s, Parkinson’s, and Huntington’s diseases. Here we provide detailed guidelines and protocols as standardised across the five collaborating laboratories of the CeBioND consortium, with additional contributions from other experts in the field.
Published: 2017

44. Hydrogen Sulfide--Mechanisms of Toxicity and Development of an Antidote.

Author: Jiang, Jingjing, Jiang, Jingjing, Chan, Adriano, Ali, Sameh, Saha, Arindam, Haushalter, Kristofer J, Lam, Wai-Ling Macrina, Glasheen, Megan, Parker, James, Brenner, Matthew, Mahon, Sari B, Patel, Hemal H, Ambasudhan, Rajesh, Lipton, Stuart A, Pilz, Renate B, Boss, Gerry R, Jiang, Jingjing, Jiang, Jingjing, Chan, Adriano, Ali, Sameh, Saha, Arindam, Haushalter, Kristofer J, Lam, Wai-Ling Macrina, Glasheen, Megan, Parker, James, Brenner, Matthew, Mahon, Sari B, Patel, Hemal H, Ambasudhan, Rajesh, Lipton, Stuart A, Pilz, Renate B, and Boss, Gerry R
Abstract: Hydrogen sulfide is a highly toxic gas-second only to carbon monoxide as a cause of inhalational deaths. Its mechanism of toxicity is only partially known, and no specific therapy exists for sulfide poisoning. We show in several cell types, including human inducible pluripotent stem cell (hiPSC)-derived neurons, that sulfide inhibited complex IV of the mitochondrial respiratory chain and induced apoptosis. Sulfide increased hydroxyl radical production in isolated mouse heart mitochondria and F2-isoprostanes in brains and hearts of mice. The vitamin B12 analog cobinamide reversed the cellular toxicity of sulfide, and rescued Drosophila melanogaster and mice from lethal exposures of hydrogen sulfide gas. Cobinamide worked through two distinct mechanisms: direct reversal of complex IV inhibition and neutralization of sulfide-generated reactive oxygen species. We conclude that sulfide produces a high degree of oxidative stress in cells and tissues, and that cobinamide has promise as a first specific treatment for sulfide poisoning.
Published: 2016

45. Hydrogen Sulfide--Mechanisms of Toxicity and Development of an Antidote.

Author: Jiang, Jingjing, Jiang, Jingjing, Chan, Adriano, Ali, Sameh, Saha, Arindam, Haushalter, Kristofer J, Lam, Wai-Ling Macrina, Glasheen, Megan, Parker, James, Brenner, Matthew, Mahon, Sari B, Patel, Hemal H, Ambasudhan, Rajesh, Lipton, Stuart A, Pilz, Renate B, Boss, Gerry R, Jiang, Jingjing, Jiang, Jingjing, Chan, Adriano, Ali, Sameh, Saha, Arindam, Haushalter, Kristofer J, Lam, Wai-Ling Macrina, Glasheen, Megan, Parker, James, Brenner, Matthew, Mahon, Sari B, Patel, Hemal H, Ambasudhan, Rajesh, Lipton, Stuart A, Pilz, Renate B, and Boss, Gerry R
Abstract: Hydrogen sulfide is a highly toxic gas-second only to carbon monoxide as a cause of inhalational deaths. Its mechanism of toxicity is only partially known, and no specific therapy exists for sulfide poisoning. We show in several cell types, including human inducible pluripotent stem cell (hiPSC)-derived neurons, that sulfide inhibited complex IV of the mitochondrial respiratory chain and induced apoptosis. Sulfide increased hydroxyl radical production in isolated mouse heart mitochondria and F2-isoprostanes in brains and hearts of mice. The vitamin B12 analog cobinamide reversed the cellular toxicity of sulfide, and rescued Drosophila melanogaster and mice from lethal exposures of hydrogen sulfide gas. Cobinamide worked through two distinct mechanisms: direct reversal of complex IV inhibition and neutralization of sulfide-generated reactive oxygen species. We conclude that sulfide produces a high degree of oxidative stress in cells and tissues, and that cobinamide has promise as a first specific treatment for sulfide poisoning.
Published: 2016

46. Role of sulfiredoxin as a peroxiredoxin-2 denitrosylase in human iPSC-derived dopaminergic neurons.

Author: Sunico, Carmen R, Sunico, Carmen R, Sultan, Abdullah, Nakamura, Tomohiro, Dolatabadi, Nima, Parker, James, Shan, Bing, Han, Xuemei, Yates, John R, Masliah, Eliezer, Ambasudhan, Rajesh, Nakanishi, Nobuki, Lipton, Stuart A, Sunico, Carmen R, Sunico, Carmen R, Sultan, Abdullah, Nakamura, Tomohiro, Dolatabadi, Nima, Parker, James, Shan, Bing, Han, Xuemei, Yates, John R, Masliah, Eliezer, Ambasudhan, Rajesh, Nakanishi, Nobuki, and Lipton, Stuart A
Abstract: Recent studies have pointed to protein S-nitrosylation as a critical regulator of cellular redox homeostasis. For example, S-nitrosylation of peroxiredoxin-2 (Prx2), a peroxidase widely expressed in mammalian neurons, inhibits both enzymatic activity and protective function against oxidative stress. Here, using in vitro and in vivo approaches, we identify a role and reaction mechanism of the reductase sulfiredoxin (Srxn1) as an enzyme that denitrosylates (thus removing -SNO) from Prx2 in an ATP-dependent manner. Accordingly, by decreasing S-nitrosylated Prx2 (SNO-Prx2), overexpression of Srxn1 protects dopaminergic neural cells and human-induced pluripotent stem cell (hiPSC)-derived neurons from NO-induced hypersensitivity to oxidative stress. The pathophysiological relevance of this observation is suggested by our finding that SNO-Prx2 is dramatically increased in murine and human Parkinson's disease (PD) brains. Our findings therefore suggest that Srxn1 may represent a therapeutic target for neurodegenerative disorders such as PD that involve nitrosative/oxidative stress.
Published: 2016

47. S-Nitrosylation Induces Structural and Dynamical Changes in a Rhodanese Family Protein.

Author: Eichmann, Cédric, Eichmann, Cédric, Tzitzilonis, Christos, Nakamura, Tomohiro, Kwiatkowski, Witek, Maslennikov, Innokentiy, Choe, Senyon, Lipton, Stuart A, Riek, Roland, Eichmann, Cédric, Eichmann, Cédric, Tzitzilonis, Christos, Nakamura, Tomohiro, Kwiatkowski, Witek, Maslennikov, Innokentiy, Choe, Senyon, Lipton, Stuart A, and Riek, Roland
Abstract: S-Nitrosylation is well established as an important post-translational regulator in protein function and signaling. However, relatively little is known about its structural and dynamical consequences. We have investigated the effects of S-nitrosylation on the rhodanese domain of the Escherichia coli integral membrane protein YgaP by NMR, X-ray crystallography, and mass spectrometry. The results show that the active cysteine in the rhodanese domain of YgaP is subjected to two competing modifications: S-nitrosylation and S-sulfhydration, which are naturally occurring in vivo. It has been observed that in addition to inhibition of the sulfur transfer activity, S-nitrosylation of the active site residue Cys63 causes an increase in slow motion and a displacement of helix 5 due to a weakening of the interaction between the active site and the helix dipole. These findings provide an example of how nitrosative stress can exert action at the atomic level.
Published: 2016

48. Quantitative Analysis of Human Pluripotency and Neural Specification by In-Depth (Phospho)Proteomic Profiling.

Author: Singec, Ilyas, Singec, Ilyas, Crain, Andrew M, Hou, Junjie, Tobe, Brian TD, Talantova, Maria, Winquist, Alicia A, Doctor, Kutbuddin S, Choy, Jennifer, Huang, Xiayu, La Monaca, Esther, Horn, David M, Wolf, Dieter A, Lipton, Stuart A, Gutierrez, Gustavo J, Brill, Laurence M, Snyder, Evan Y, Singec, Ilyas, Singec, Ilyas, Crain, Andrew M, Hou, Junjie, Tobe, Brian TD, Talantova, Maria, Winquist, Alicia A, Doctor, Kutbuddin S, Choy, Jennifer, Huang, Xiayu, La Monaca, Esther, Horn, David M, Wolf, Dieter A, Lipton, Stuart A, Gutierrez, Gustavo J, Brill, Laurence M, and Snyder, Evan Y
Abstract: Controlled differentiation of human embryonic stem cells (hESCs) can be utilized for precise analysis of cell type identities during early development. We established a highly efficient neural induction strategy and an improved analytical platform, and determined proteomic and phosphoproteomic profiles of hESCs and their specified multipotent neural stem cell derivatives (hNSCs). This quantitative dataset (nearly 13,000 proteins and 60,000 phosphorylation sites) provides unique molecular insights into pluripotency and neural lineage entry. Systems-level comparative analysis of proteins (e.g., transcription factors, epigenetic regulators, kinase families), phosphorylation sites, and numerous biological pathways allowed the identification of distinct signatures in pluripotent and multipotent cells. Furthermore, as predicted by the dataset, we functionally validated an autocrine/paracrine mechanism by demonstrating that the secreted protein midkine is a regulator of neural specification. This resource is freely available to the scientific community, including a searchable website, PluriProt.
Published: 2016

49. Protein S-Nitrosylation as a Therapeutic Target for Neurodegenerative Diseases.

Author: Nakamura, Tomohiro, Nakamura, Tomohiro, Lipton, Stuart A, Nakamura, Tomohiro, Nakamura, Tomohiro, and Lipton, Stuart A
Abstract: At physiological levels, nitric oxide (NO) contributes to the maintenance of normal neuronal activity and survival, thus serving as an important regulatory mechanism in the central nervous system. By contrast, accumulating evidence suggests that exposure to environmental toxins or the normal aging process can trigger excessive production of reactive oxygen/nitrogen species (such as NO), contributing to the etiology of several neurodegenerative diseases. We highlight here protein S-nitrosylation, resulting from covalent attachment of an NO group to a cysteine thiol of the target protein, as a ubiquitous effector of NO signaling in both health and disease. We review our current understanding of this redox-dependent post-translational modification under neurodegenerative conditions, and evaluate how targeting dysregulated protein S-nitrosylation can lead to novel therapeutics.
Published: 2016

50. Application of FDA-Approved Memantine and Newer NitroMemantine Derivatives to Treat Neurological Manifestations in Rodent Models of Tuberous Sclerosis Complex

Author: SANFORD-BURNHAM MEDICAL RESEARCH INST LA JOLLA CA, Lipton, Stuart A, SANFORD-BURNHAM MEDICAL RESEARCH INST LA JOLLA CA, and Lipton, Stuart A
Abstract: The quality of life for those afflicted by Tuberous Sclerosis Complex (TSC) is affected by intellectual and neurological disabilities mediated in part by excessive glutamatergic activity in the brain. It is important to develop rational and effective therapies for early postnatal or even embryonic treatment of these neurological manifestations. Towards this goal, we propose to investigate if administration of the FDA-approved drug, Memantine, an uncompetitive/fast off-rate antagonist of the Nmethyl- D-aspartate-type glutamate receptor, and its improved derivative, NitroMemantine, ameliorate neurological complications in mouse models of TSC. During Year 01 of the grant, we obtained favorable results for Memantine on electrophysiological and neurobehavioral tests in Tsc2+/- mice. Treatment of Tsc2+/- mice with Memantine improved long-term potentiation (LTP), an electrical correlate of learning and memory, in the CA1 region of the hippocampus. Additionally, treatment of Tsc2+/- mice with Memantine showed a trend towards restoration of the ability to locate the platform in the Morris water maze, a neurobehavioral test of hippocampal memory. In Year 02, we plan to further validate and extend our findings with Memantine and critically test the efficacy of NitroMemantine. We expect that NitroMemantine will offer an advantage over Memantine in TSC model mice, as we have previously demonstrated in other neurological disorders., The original document contains color images.
Published: 2014

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