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1. Functionality Determinants and Pore-level Quantitative Structure-Activity Relationship (QSAR) Approach for Water Permeation Rate in Aquaporins

Author

Galano-Frutos, Juan José, Bergamasco, Luca, Vigo, Paolo, Morciano, Matteo, Fasano, Matteo, Pirolli, Davide, Chiavazzo, Eliodoro, and de Rosa, Maria Cristina

Subjects
Quantitative Biology - Biomolecules
Abstract

Aquaporins play a key role for the regulation of water transport and solute selectivity in biological cells and tissues. Due to their unique properties, during the last years aquaporins (AQPs) have attracted increasing interest for their use in the development of biomimetic membranes for water filtration. Motivated by this fascinating application, and the need for reliable methodologies to rationalize the design of AQPs or other biomimetic molecules with targeted filtration properties, we conduct in this work an all-round analysis of their structural features to provide crucial insights into the key determinants of functionality of these relevant biomolecules. Particularly, we analyze -- on a selected set of experimentally-resolved AQP structures -- the composition and peculiarities of their NPA and Selectivity Filter (SF) motifs, the overall structural and sequence similarities between them, their pore shape and the residue-level pore-lining composition. Then, AQPs' pore structural and physico-chemical descriptors are put into correlation with available data on experimental permeation rate, within the context of a pore-level QSAR modeling. The approach, presented here as a methodological proof of concept, enables the identification of key -- potentially novel -- features related to water permeability, which could contribute to a deeper residue-level understanding of AQP filtering properties. Potential beneficiary areas include the rational design of optimized AQP-based biomimetic membranes and research into the molecular mechanisms underlying AQP-related diseases.

Published
2024

6. In-silico guided chemical exploration of KDM4A fragments hits

Author

Lombino, Jessica, Vallone, Rosario, Cimino, Maura, Gulotta, Maria Rita, De Simone, Giada, Morando, Maria Agnese, Sabbatella, Raffaele, Di Martino, Simona, Fogazza, Mario, Sarno, Federica, Coronnello, Claudia, De Rosa, Maria, Cipollina, Chiara, Altucci, Lucia, Perricone, Ugo, and Alfano, Caterina

Published
2023
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11. Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons

Author

Al-Dalahmah, Osama, Lam, Matti, McInvale, Julie J., Qu, Wenhui, Nguyen, Trang, Mun, Jeong-Yeon, Kwon, Sam, Ifediora, Nkechime, Mahajan, Aayushi, Humala, Nelson, Winters, Tristan, Angeles, Ellen, Jakubiak, Kelly A., Kühn, Rebekka, Kim, Yoon A., De Rosa, Maria Caterina, Doege, Claudia A., Paryani, Fahad, Flowers, Xena, Dovas, Athanassios, Mela, Angeliki, Lu, Hong, DeTure, Michael A., Vonsattel, Jean Paul, Wszolek, Zbigniew K., Dickson, Dennis W., Kuhlmann, Tanja, Zaehres, Holm, Schöler, Hans R., Sproul, Andrew A., Siegelin, Markus D., De Jager, Philip L., Goldman, James E., Menon, Vilas, Canoll, Peter, and Hargus, Gunnar

Published
2024
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13. Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development

Author

Wang, Liheng, De Solis, Alain J, Goffer, Yossef, Birkenbach, Kathryn E, Engle, Staci E, Tanis, Ross, Levenson, Jacob M, Li, Xueting, Rausch, Richard, Purohit, Manika, Lee, Jen-Yi, Tan, Jerica, De Rosa, Maria Caterina, Doege, Claudia A, Aaron, Holly L, Martins, Gabriela J, Brüning, Jens C, Egli, Dieter, Costa, Rui, Berbari, Nicolas, Leibel, Rudolph L, and Stratigopoulos, George

Subjects
Obesity, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Genetics, Neurosciences, Nutrition, Pediatric, Stem Cell Research - Induced Pluripotent Stem Cell, Stem Cell Research, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Embryonic development, Metabolism, NPY, Neuroscience
Abstract

Intronic polymorphisms in the α-ketoglutarate-dependent dioxygenase gene (FTO) that are highly associated with increased body weight have been implicated in the transcriptional control of a nearby ciliary gene, retinitis pigmentosa GTPase regulator-interacting protein-1 like (RPGRIP1L). Previous studies have shown that congenital Rpgrip1l hypomorphism in murine proopiomelanocortin (Pomc) neurons causes obesity by increasing food intake. Here, we show by congenital and adult-onset Rpgrip1l deletion in Pomc-expressing neurons that the hyperphagia and obesity are likely due to neurodevelopmental effects that are characterized by a reduction in the Pomc/Neuropeptide Y (Npy) neuronal number ratio and marked increases in arcuate hypothalamic-paraventricular hypothalamic (ARH-PVH) axonal projections. Biallelic RPGRIP1L mutations result in fewer cilia-positive human induced pluripotent stem cell-derived (iPSC-derived) neurons and blunted responses to Sonic Hedgehog (SHH). Isogenic human ARH-like embryonic stem cell-derived (ESc-derived) neurons homozygous for the obesity-risk alleles at rs8050136 or rs1421085 have decreased RPGRIP1L expression and have lower numbers of POMC neurons. RPGRIP1L overexpression increases POMC cell number. These findings suggest that apparently functional intronic polymorphisms affect hypothalamic RPGRIP1L expression and impact development of POMC neurons and their derivatives, leading to hyperphagia and increased adiposity.

Published
2019

17. A journey to ‘tame a small metazoan organism’, seen through the artistic eyes of C. elegans researchers

Author

Gourgou, Eleni, primary, Willis, Alexandra R., additional, Giunti, Sebastian, additional, De Rosa, Maria J., additional, Charlesworth, Amanda G., additional, Hernandez Lima, Mirella, additional, Glater, Elizabeth, additional, Soo, Sonja, additional, Pereira, Bianca, additional, Akbaş, Kübra, additional, Deb, Anushka, additional, Kamak, Madhushree, additional, Moyle, Mark W., additional, Traa, Annika, additional, Singhvi, Aakanksha, additional, Sural, Surojit, additional, and Jin, Eugene Jennifer, additional

Published
2022
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19. A Modified Basophil Activation Test for the Clinical Management of Immediate Hypersensitivity Reactions to Paclitaxel: A Proof-of-Concept Study

Author

La Sorda, Marilena, primary, Fossati, Marco, additional, Graffeo, Rosalia, additional, Ferraironi, Manuela, additional, De Rosa, Maria Cristina, additional, Buzzonetti, Alexia, additional, Righino, Benedetta, additional, Zampetti, Nicole, additional, Fattorossi, Andrea, additional, Nucera, Eleonora, additional, Aruanno, Arianna, additional, Ferrandina, Gabriella, additional, Apostol, Adriana Ionelia, additional, Buonomo, Alessandro, additional, Scambia, Giovanni, additional, Sanguinetti, Maurizio, additional, and Battaglia, Alessandra, additional

Published
2023
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21. Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits

Author

Pahl, Matthew C., Doege, Claudia A., Hodge, Kenyaita M., Littleton, Sheridan H., Leonard, Michelle E., Lu, Sumei, Rausch, Rick, Pippin, James A., De Rosa, Maria Caterina, Basak, Alisha, Bradfield, Jonathan P., Hammond, Reza K., Boehm, Keith, Berkowitz, Robert I., Lasconi, Chiara, Su, Chun, Chesi, Alessandra, Johnson, Matthew E., Wells, Andrew D., Voight, Benjamin F., Leibel, Rudolph L., Cousminer, Diana L., and Grant, Struan F. A.

Published
2021
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24. A community effort in SARS‐CoV‐2 drug discovery

Author

Schimunek, Johannes, primary, Seidl, Philipp, additional, Elez, Katarina, additional, Hempel, Tim, additional, Le, Tuan, additional, Noé, Frank, additional, Olsson, Simon, additional, Raich, Lluís, additional, Winter, Robin, additional, Gokcan, Hatice, additional, Gusev, Filipp, additional, Gutkin, Evgeny M., additional, Isayev, Olexandr, additional, Kurnikova, Maria G., additional, Narangoda, Chamali H., additional, Zubatyuk, Roman, additional, Bosko, Ivan P., additional, Furs, Konstantin V., additional, Karpenko, Anna D., additional, Kornoushenko, Yury V., additional, Shuldau, Mikita, additional, Yushkevich, Artsemi, additional, Benabderrahmane, Mohammed, additional, Bousquet-Melou, Patrick, additional, Bureau, Ronan, additional, Charton, Beatrice, additional, Cirou, Bertrand, additional, Gil, Gérard, additional, Allen, William J., additional, Sirimulla, Suman, additional, Watowich, Stanley, additional, Antonopoulos, Nick, additional, Epitropakis, Nikolaos, additional, Krasoulis, Agamemnon, additional, Pitsikalis, Vassilis, additional, Theodorakis, Stavros, additional, Kozlovskii, Igor, additional, Maliutin, Anton, additional, Medvedev, Alexander, additional, Popov, Petr, additional, Zaretckii, Mark, additional, Eghbal-zadeh, Hamid, additional, Halmich, Christina, additional, Hochreiter, Sepp, additional, Mayr, Andreas, additional, Ruch, Peter, additional, Widrich, Michael, additional, Berenger, Francois, additional, Kumar, Ashutosh, additional, Yamanishi, Yoshihiro, additional, Zhang, Kam, additional, Bengio, Emmanuel, additional, Bengio, Yoshua, additional, Jain, Moksh, additional, Korablyov, Maksym, additional, Liu, Cheng-Hao, additional, Gilles, Marcous, additional, Glaab, Enrico, additional, Barnsley, Kelly, additional, Iyengar, Suhasini M., additional, Ondrechen, Mary Jo, additional, Haupt, V. Joachim, additional, Kaiser, Florian, additional, Schroeder, Michael, additional, Pugliese, Luisa, additional, Albani, Simone, additional, Athanasiou, Christina, additional, Beccari, Andrea, additional, Carloni, Paolo, additional, D'Arrigo, Giulia, additional, Gianquinto, Eleonora, additional, Goßen, Jonas, additional, Hanke, Anton, additional, Joseph, Benjamin P., additional, Kokh, Daria B., additional, Kovachka, Sandra, additional, Manelfi, Candida, additional, Mukherjee, Goutam, additional, Muñiz-Chicharro, Abraham, additional, Musiani, Francesco, additional, Nunes-Alves, Ariane, additional, Paiardi, Giulia, additional, Rossetti, Giulia, additional, Sadiq, S. Kashif, additional, Spyrakis, Francesca, additional, Talarico, Carmine, additional, Tsengenes, Alexandros, additional, Wade, Rebecca, additional, Copeland, Conner, additional, Gaiser, Jeremiah, additional, Olson, Daniel R., additional, Roy, Amitava, additional, Venkatraman, Vishwesh, additional, Wheeler, Travis J., additional, Arthanari, Haribabu, additional, Blaschitz, Klara, additional, Cespugli, Marco, additional, Durmaz, Vedat, additional, Fackeldey, Konstantin, additional, Fischer, Patrick D., additional, Gorgulla, Christoph, additional, Gruber, Christian, additional, Gruber, Karl, additional, Hetmann, Michael, additional, Kinney, Jamie E., additional, Das, Krishna M. Padmanabha, additional, Pandita, Shreya, additional, Singh, Amit, additional, Steinkellner, Georg, additional, Tesseyre, Guilhem, additional, Wagner, Gerhard, additional, Wang, Zi-Fu, additional, Yust, Ryan J., additional, Druzhilovskiy, Dmitry S., additional, Filimonov, Dmitry, additional, Pogodin, Pavel V., additional, Poroikov, Vladimir, additional, Rudik, Anastassia V., additional, Stolbov, Leonid A., additional, Veselovsky, Alexander V., additional, De Rosa, Maria, additional, Simone, Giada De, additional, Gulotta, Maria R., additional, Lombino, Jessica, additional, Mekni, Nedra, additional, Perricone, Ugo, additional, Casini, Arturo, additional, Embree, Amanda, additional, Gordon, D. Benjamin, additional, Lei, David, additional, Pratt, Katelin, additional, Voigt, Christopher A., additional, Chen, Kuang-Yu, additional, Jacob, Yves, additional, Krischuns, Tim, additional, Lafaye, Pierre, additional, Zettor, Agnès, additional, Rodríguez, M. Luis, additional, White, Kris M., additional, Fearon, Daren, additional, von Delft, Frank, additional, Walsh, Martin A., additional, Horvath, Dragos, additional, Brooks, Charles L., additional, Falsafi, Babak, additional, Ford, Bryan, additional, García-Sastre, Adolfo, additional, Lee, Sang Yup, additional, Naffakh, Nadia, additional, Varnek, Alexandre, additional, Klambauer, Guenter, additional, and Hermans, Thomas M., additional

Published
2023
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25. Identifying and characterizing novel HSP90 inhibitors with senolytic activity in a hormone-induced breast cancer-senescence model

Author

Cis, Luca, primary, Atlante, Sandra, additional, De, Martino Sara, additional, Cencioni, Chiara, additional, Aiello, Aurora, additional, Pirolli, Davide, additional, Malavolta, Marco, additional, Nanni, Simona, additional, De, Rosa Maria Cristina, additional, Gaetano, Carlo, additional, and Farsetti, Antonella, additional

Published
2023
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30. Functional identity of hypothalamic melanocortin neurons depends on Tbx3

Author

Quarta, Carmelo, Fisette, Alexandre, Xu, Yanjun, Colldén, Gustav, Legutko, Beata, Tseng, Yu-Ting, Reim, Alexander, Wierer, Michael, De Rosa, Maria Caterina, Klaus, Valentina, Rausch, Rick, Thaker, Vidhu V., Graf, Elisabeth, Strom, Tim M., Poher, Anne-Laure, Gruber, Tim, Le Thuc, Ophélia, Cebrian-Serrano, Alberto, Kabra, Dhiraj, Bellocchio, Luigi, Woods, Stephen C., Pflugfelder, Gert O., Nogueiras, Rubén, Zeltser, Lori, Grunwald Kadow, Ilona C., Moon, Anne, García-Cáceres, Cristina, Mann, Matthias, Treier, Mathias, Doege, Claudia A., and Tschöp, Matthias H.

Published
2019
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38. Hearing Loss: Genetic Testing, Current Advances and the Situation in Latin America.

Author

De Rosa, Maria Agustina, Bernardi, Maria T., Kleppe, Soledad, and Walz, Katherina

Subjects
*HEARING disorders, *GENETIC testing, *AUDIOMETRY, *SENSORINEURAL hearing loss, *HUMAN abnormalities
Abstract

Congenital hearing loss is the most common birth defect, estimated to affect 2–3 in every 1000 births, with ~50–60% of those related to genetic causes. Technological advances enabled the identification of hundreds of genes related to hearing loss (HL), with important implications for patients, their families, and the community. Despite these advances, in Latin America, the population with hearing loss remains underdiagnosed, with most studies focusing on a single locus encompassing the GJB2/GJB6 genes. Here we discuss how current and emerging genetic knowledge has the potential to alter the approach to diagnosis and management of hearing loss, which is the current situation in Latin America, and the barriers that still need to be overcome. [ABSTRACT FROM AUTHOR]

Published
2024
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40. Invasive Assessment of Coronary Microcirculation: A State-of-the-Art Review.

Author

Ciaramella, Luca, Di Serafino, Luigi, Mitrano, Lucia, De Rosa, Maria Luisa, Carbone, Carlo, Rea, Francesco Saverio, Monaco, Salvatore, Scalamogna, Maria, Cirillo, Plinio, and Esposito, Giovanni

Subjects
MICROCIRCULATION, MICROCIRCULATION disorders, MYOCARDIAL ischemia, CORONARY artery disease, SYMPTOMS
Abstract

A significant proportion of patients presenting with signs and symptoms of myocardial ischemia have no "significant" epicardial disease; thereby, the assessment of coronary microcirculation gained an important role in improving diagnosis and guiding therapy. In fact, coronary microvascular dysfunction (CMD) could be found in a large proportion of these patients, supporting both symptoms and signs of myocardial ischemia. However, CMD represents a diagnostic challenge for two main reasons: (1) the small dimension of the coronary microvasculature prevents direct angiographic visualization, and (2) despite the availability of specific diagnostic tools, they remain invasive and underused in the current clinical practice. For these reasons, CMD remains underdiagnosed, and most of the patients remain with no specific treatment and quality-of-life-limiting symptoms. Of note, recent evidence suggests that a "full physiology" approach for the assessment of the whole coronary vasculature may offer a significant benefit in terms of symptom improvement among patients presenting with ischemia and non-obstructive coronary artery disease. We analyze the pathophysiology of coronary microvascular dysfunction, providing the readers with a guide for the invasive assessment of coronary microcirculation, together with the available evidence supporting its use in clinical practice. [ABSTRACT FROM AUTHOR]

Published
2024
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41. Community-acquired pneumonia severity assessment tools in patients hospitalized with COVID-19: a validation and clinical applicability study

Author

Bortolotto, Alexandre Lemos, Müller Veiga, Alicia Dudy, Bellintani, Arthur Petrillo, Fantinatti, Beatriz Larios, Nicolao, Bianca Ruiz, Caldeira, Bruna Tolentino, Umehara Juck, Carlos Eduardo, Bueno, Cauê Gasparatto, Takamune, Diego Juniti, Guidotte, Diogo Visconti, D'Souza, Edwin Albert, Oliveira Silva, Emily Cristine, Brito Miyaguchi, Erika Thiemy, Gomes da Silva, Ester Minã, Santos Moreira, Everton Luis, Fonseca e Silva, Fernanda Máximo, de Paula Maroni Escudeiro, Gabriel, Travessini, Gabriel, Costa, Giovanna Babikian, Tibucheski dos Santos, Henrique, Omori, Isabela Harumi, Baptista, João Martelleto, Afonso Nascimento, João Pedro, de Góes Campos, Laura, Lima, Ligia Trombetta, Boscolo, Luiza, Adsuara Pandolfi, Manuela Cristina, de Oliveira Silva, Marcelo, Sanches, Marcelo Petrof, Saad Menezes, Maria Clara, Gonçalves Cimatti De Calasans, Mariana Mendes, Lima de Faria, Matheus Finardi, Bezerra Martins, Nilo Arthur, Albuquerque de Moura, Patricia, Araújo Simões, Pedro Antonio, Luna, Rafael Berenguer, Nishiaka, Renata Kan, Miléo, Rodrigo Cezar, de Souza Abreu, Rodrigo, Toccoli, Rodrigo Werner, Monsalvarga, Tales Cabral, Brito Medeiros, Vitor Macedo, Filippo Fernandes, Yasmine Souza, Simões, Ademar Lima, Tavares, Andrew Araujo, Carvalho de Alves Pereira, Clara, Ribeiro, Daniel Rodrigues, Dias de Francesco, Danilo, Emerenciano, Debora Lopes, Pires de Campos, Eduardo Mariani, Moreira, Felipe Liger, Bortoleto, Felipe Mouzo, Martinez, Gabriel, Wiebelling da Silva, Geovane, Martins, Gustavo Biz, Leite Fortes, Julio Cesar, Dias Barreto, Lucas Gonçalves, Silva de Rosa, Maria Lorraine, Ursoline do Nascimento, Mauricio, Pisciolaro, Rafael Faria, Xavier, Rodolfo Affonso, Barbosa de Souza, Stefany Franhan, Lisboa Netto, Thiago Areas, Ribeiro, Sabrina, Faria, Carine, Rahhal, Hassam, Padrão, Eduardo, Valente, Fernando, Padovan Chio, Yago Henrique, Gomez Gomez, Luz Marina, Lazar Neto, Felippe, Marino, Lucas Oliveira, Torres, Antoni, Cilloniz, Catia, Meirelles Marchini, Julio Flavio, Garcia de Alencar, Julio Cesar, Palomeque, Andrea, Albacar, Núria, Brandão Neto, Rodrigo Antônio, Souza, Heraldo Possolo, and Ranzani, Otavio T.

Published
2021
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43. A community effort to discover small molecule SARS-CoV-2 inhibitors

Author

Schimunek, Johannes, primary, Seidl, Philipp, additional, Elez, Katarina, additional, Hempel, Tim, additional, Le, Tuan, additional, Noé, Frank, additional, Olsson, Simon, additional, Raich, Lluís, additional, Winter, Robin, additional, Gokcan, Hatice, additional, Gusev, Filipp, additional, Gutkin, Evgeny M., additional, Isayev, Olexandr, additional, Kurnikova, Maria G., additional, Narangoda, Chamali H., additional, Zubatyuk, Roman, additional, Bosko, Ivan P., additional, Furs, Konstantin V., additional, Karpenko, Anna D., additional, Kornoushenko, Yury V., additional, Shuldau, Mikita, additional, Yushkevich, Artsemi, additional, Benabderrahmane, Mohammed B., additional, Bousquet-Melou, Patrick, additional, Bureau, Ronan, additional, Charton, Beatrice, additional, Cirou, Bertrand C., additional, Gil, Gérard, additional, Allen, William J., additional, Sirimulla, Suman, additional, Watowich, Stanley, additional, Antonopoulos, Nick A., additional, Epitropakis, Nikolaos E., additional, Krasoulis, Agamemnon K., additional, Pitsikalis, Vassilis P., additional, Theodorakis, Stavros T., additional, Kozlovskii, Igor, additional, Maliutin, Anton, additional, Medvedev, Alexander, additional, Popov, Petr, additional, Zaretckii, Mark, additional, Eghbal-zadeh, Hamid, additional, Halmich, Christina, additional, Hochreiter, Sepp, additional, Mayr, Andreas, additional, Ruch, Peter, additional, Widrich, Michael, additional, Berenger, Francois, additional, Kumar, Ashutosh, additional, Yamanishi, Yoshihiro, additional, Zhang, Kam Y.J., additional, Bengio, Emmanuel, additional, Bengio, Yoshua, additional, Jain, Moksh J., additional, Korablyov, Maksym, additional, Liu, Cheng-Hao, additional, Marcou, Gilles, additional, Glaab, Enrico, additional, Barnsley, Kelly, additional, Iyengar, Suhasini M., additional, Ondrechen, Mary Jo, additional, Haupt, V. Joachim, additional, Kaiser, Florian, additional, Schroeder, Michael, additional, Pugliese, Luisa, additional, Albani, Simone, additional, Athanasiou, Christina, additional, Beccari, Andrea, additional, Carloni, Paolo, additional, D'Arrigo, Giulia, additional, Gianquinto, Eleonora, additional, Goßen, Jonas, additional, Hanke, Anton, additional, Joseph, Benjamin P., additional, Kokh, Daria B., additional, Kovachka, Sandra, additional, Manelfi, Candida, additional, Mukherjee, Goutam, additional, Muñiz-Chicharro, Abraham, additional, Musiani, Francesco, additional, Nunes-Alves, Ariane, additional, Paiardi, Giulia, additional, Rossetti, Giulia, additional, Sadiq, S. Kashif, additional, Spyrakis, Francesca, additional, Talarico, Carmine, additional, Tsengenes, Alexandros, additional, Wade, Rebecca C., additional, Copeland, Conner, additional, Gaiser, Jeremiah, additional, Olson, Daniel R., additional, Roy, Amitava, additional, Venkatraman, Vishwesh, additional, Wheeler, Travis J., additional, Arthanari, Haribabu, additional, Blaschitz, Klara, additional, Cespugli, Marco, additional, Durmaz, Vedat, additional, Fackeldey, Konstantin, additional, Fischer, Patrick D., additional, Gorgulla, Christoph, additional, Gruber, Christian, additional, Gruber, Karl, additional, Hetmann, Michael, additional, Kinney, Jamie E., additional, Padmanabha Das, Krishna M., additional, Pandita, Shreya, additional, Singh, Amit, additional, Steinkellner, Georg, additional, Tesseyre, Guilhem, additional, Wagner, Gerhard, additional, Wang, Zi-Fu, additional, Yust, Ryan J., additional, Druzhilovskiy, Dmitry S., additional, Filimonov, Dmitry A., additional, Pogodin, Pavel V., additional, Poroikov, Vladimir, additional, Rudik, Anastassia V., additional, Stolbov, Leonid A., additional, Veselovsky, Alexander V., additional, De Rosa, Maria, additional, De Simone, Giada, additional, Gulotta, Maria R., additional, Lombino, Jessica, additional, Mekni, Nedra, additional, Perricone, Ugo, additional, Casini, Arturo, additional, Embree, Amanda, additional, Gordon, D. Benjamin, additional, Lei, David, additional, Pratt, Katelin, additional, Voigt, Christopher A., additional, Chen, Kuang-Yu, additional, Jacob, Yves, additional, Krischuns, Tim, additional, Lafaye, Pierre, additional, Zettor, Agnès, additional, Rodríguez, M. Luis, additional, White, Kris M., additional, Fearon, Daren, additional, Von Delft, Frank, additional, Walsh, Martin A., additional, Horvath, Dragos, additional, Brooks III, Charles L., additional, Falsafi, Babak, additional, Ford, Bryan, additional, García-Sastre, Adolfo, additional, Lee, Sang Yup, additional, Naffakh, Nadia, additional, Varnek, Alexandre, additional, Klambauer, Günter, additional, and Hermans, Thomas M., additional

Published
2023
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45. Bardet-Biedl syndrome proteins regulate intracellular signaling and neuronal function in patient-specific iPSC-derived neurons

Author

Wang, Liheng, Liu, Yang, Stratigopoulos, George, Panigrahi, Sunil, Sui, Lina, Zhang, Yiying, Leduc, Charles A., Glover, Hannah J., De Rosa, Maria Caterina, Burnett, Lisa C., Williams, Damian J., Shang, Linshan, Goland, Robin, Tsang, Stephen H., Wardlaw, Sharon, Egli, Dieter, Zheng, Deyou, Doege, Claudia A., and Leibel, Rudolph L.

Subjects
Gene mutations -- Health aspects, Obesity -- Complications and side effects, Stem cells -- Usage, Bardet-Biedl syndrome -- Models, Cellular proteins -- Health aspects, Health care industry
Abstract

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and is characterized by hyperphagic obesity. To investigate the molecular basis of obesity in human BBS, we developed a cellular model of BBS using induced pluripotent stem cell-derived (iPSC-derived) hypothalamic arcuate-like neurons. BBS mutations [BBS1.sup.M390R] and BBS[10.sup.C91fsX95] did not affect neuronal differentiation efficiency but caused morphological defects, including impaired neurite outgrowth and longer primary cilia. Single-cell RNA sequencing of [BBS1.sup.M390R] hypothalamic neurons identified several downregulated pathways, including insulin and cAMP signaling and axon guidance. Additional studies demonstrated that [BBS1.sup.M390R] and BBS[10.sup.C91fsX95] mutations impaired insulin signaling in both human fibroblasts and iPSC-derived neurons. Overexpression of intact BBS10 fully restored insulin signaling by restoring insulin receptor tyrosine phosphorylation in BBS[10.sup.C91fsX95] neurons. Moreover, mutations in BBS1 and BBS10 impaired leptin-mediated p-STAT3 activation in iPSC-derived hypothalamic neurons. Correction of the BBS mutation by CRISPR rescued leptin signaling. POMC expression and neuropeptide production were decreased in [BBS1.sup.M390R] and BBS[10.sup.C91fsX95] iPSC-derived hypothalamic neurons. In the aggregate, these data provide insights into the anatomic and functional mechanisms by which components of the BBSome in CNS primary cilia mediate effects on energy homeostasis., Introduction Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by severe, early-onset obesity, as well as an array of other diagnostic features typical of ciliopathies including polydactyly, retinal degeneration, [...]

Published
2021
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