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1. Biofabrication and biomanufacturing in Ireland and the UK

Author

Murphy, Jack F., Lavelle, Martha, Asciak, Lisa, Burdis, Ross, Levis, Hannah J., Ligorio, Cosimo, McGuire, Jamie, Polleres, Marlene, Smith, Poppy O., Tullie, Lucinda, Uribe-Gomez, Juan, Chen, Biqiong, Dawson, Jonathan I., Gautrot, Julien E., Hooper, Nigel M., Kelly, Daniel J., Li, Vivian S. W., Mata, Alvaro, Pandit, Abhay, Phillips, James B., Shu, Wenmiao, Stevens, Molly M., Williams, Rachel L., Armstrong, James P. K., and Huang, Yan Yan Shery

Published
2024
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2. Proteolysis of tau by granzyme A in tauopathies generates fragments that are aggregation prone.

Author

Quinn, James P., Fisher, Kate, Corbett, Nicola, Warwood, Stacey, Knight, David, Kellett, Katherine A. B., and Hooper, Nigel M.

Subjects
PROGRESSIVE supranuclear palsy, CYTOTOXIC T cells, ALZHEIMER'S disease, TAUOPATHIES, POST-translational modification, NEUROFIBRILLARY tangles, TAU proteins
Abstract

Tauopathies, including Alzheimer's disease, corticobasal degeneration and progressive supranuclear palsy, are characterised by the aggregation of tau into insoluble neurofibrillary tangles in the brain. Tau is subject to a range of post-translational modifications, including proteolysis, that can promote its aggregation. Neuroinflammation is a hallmark of tauopathies and evidence is growing for a role of CD8+ T cells in disease pathogenesis. CD8+ T cells release granzyme proteases but what role these proteases play in neuronal dysfunction is currently lacking. Here, we identified that granzyme A (GzmA) is present in brain tissue and proteolytically cleaves tau. Mass spectrometric analysis of tau fragments produced on digestion of tau with GzmA identified three cleavage sites at R194-S195, R209-S210 and K240-S241. Mutation of the critical Arg or Lys residues at the cleavage sites in tau or chemical inhibition of GzmA blocked the proteolysis of tau by GzmA. Development of a semi-targeted mass spectrometry approach identified peptides in tauopathy brain tissue corresponding to proteolysis by GzmA at R209-S210 and K240-S241 in tau. When expressed in cells the GzmA-cleaved C-terminal fragments of tau were highly phosphorylated and aggregated upon incubation of the cells with tauopathy brain seed. The C-terminal fragment tau195–441 was able to transfer between cells and promote aggregation of tau in acceptor cells, indicating the propensity for such tau fragments to propagate between cells. Collectively, these results raise the possibility that GzmA, released from infiltrating cytotoxic CD8+ T cells, proteolytically cleaves tau into fragments that may contribute to its pathological properties in tauopathies. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil

Author

Sellers, Katherine J., Elliott, Christina, Jackson, Joshua, Ghosh, Anshua, Ribe, Elena, Rojo, Ana I., Jarosz-Griffiths, Heledd H., Watson, Iain A., Xia, Weiming, Semenov, Mikhail, Morin, Peter, Hooper, Nigel M., Porter, Rod, Preston, Jane, Al-Shawi, Raya, Baillie, George, Lovestone, Simon, Cuadrado, Antonio, Harte, Michael, Simons, Paul, Srivastava, Deepak P., and Killick, Richard

Published
2018
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10. Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation.

Author

Aldworth, Harry and Hooper, Nigel M.

Subjects
*LIPOPROTEIN receptors, *UBIQUITIN ligases, *CHOLESTEROL, *METABOLIC regulation, *CELL membranes, *PRESENILINS
Abstract

The amount of the low-density lipoprotein receptor (LDLR) on the surface of hepatocytes is the primary determinant of plasma low-density lipoprotein (LDL)-cholesterol level. Although the synthesis and cellular trafficking of the LDLR have been well-documented, there is growing evidence of additional post-translational mechanisms that regulate or fine tune the surface availability of the LDLR, thus modulating its ability to bind and internalise LDL-cholesterol. Proprotein convertase subtilisin/kexin type 9 and the asialoglycoprotein receptor 1 both independently interact with the LDLR and direct it towards the lysosome for degradation. While ubiquitination by the E3 ligase inducible degrader of the LDLR also targets the receptor for lysosomal degradation, ubiquitination of the LDLR by a different E3 ligase, RNF130, redistributes the receptor away from the plasma membrane. The activity of the LDLR is also regulated by proteolysis. Proteolytic cleavage of the transmembrane region of the LDLR by γ-secretase destabilises the receptor, directing it to the lysosome for degradation. Shedding of the extracellular domain of the receptor by membrane-type 1 matrix metalloprotease and cleavage of the receptor in its LDL-binding domain by bone morphogenetic protein-1 reduces the ability of the LDLR to bind and internalise LDL-cholesterol at the cell surface. A better understanding of how the activity of the LDLR is regulated will not only unravel the complex biological mechanisms controlling LDL-cholesterol metabolism but also could help inform the development of alternative pharmacological intervention strategies for the treatment of hypercholesterolaemia. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Induced pluripotent stem cell model revealed impaired neurovascular interaction in genetic small vessel disease Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Author

Zhang, Wenjun, Zhao, Xiangjun, Qi, Xuewei, Kimber, Susan J., Hooper, Nigel M., and Wang, Tao

Abstract

Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common genetic small vessel disease caused by variants in the NOTCH3 gene. Patients with CADASIL experience recurrent strokes, developing into cognitive defect and vascular dementia. CADASIL is a late-onset vascular condition, but migraine and brain MRI lesions appear in CADASIL patients as early as their teens and twenties, suggesting an abnormal neurovascular interaction at the neurovascular unit (NVU) where microvessels meet the brain parenchyma.Methods: To understand the molecular mechanisms of CADASIL, we established induced pluripotent stem cell (iPSC) models from CADASIL patients and differentiated the iPSCs into the major NVU cell types including brain microvascular endothelial-like cells (BMECs), vascular mural cells (MCs), astrocytes and cortical projection neurons. We then built an in vitro NVU model by co-culturing different neurovascular cell types in Transwells and evaluated the blood brain barrier (BBB) function by measuring transendothelial electrical resistance (TEER).Results: Results showed that, while the wild-type MCs, astrocytes and neurons could all independently and significantly enhance TEER of the iPSC-BMECs, such capability of MCs from iPSCs of CADASIL patients was significantly impaired. Additionally, the barrier function of the BMECs from CADASIL iPSCs was significantly decreased, accompanied with disorganized tight junctions in iPSC-BMECs, which could not be rescued by the wild-type MCs or sufficiently rescued by the wild-type astrocytes and neurons.Discussion: Our findings provide new insight into early disease pathologies on the neurovascular interaction and BBB function at the molecular and cellular levels for CADASIL, which helps inform future therapeutic development.

Published
2023
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16. Author Correction: Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Author

Kunkle, Brian W., Grenier-Boley, Benjamin, Sims, Rebecca, Bis, Joshua C., Damotte, Vincent, Naj, Adam C., Boland, Anne, Vronskaya, Maria, van der Lee, Sven J., Amlie-Wolf, Alexandre, Bellenguez, Céline, Frizatti, Aura, Chouraki, Vincent, Martin, Eden R., Sleegers, Kristel, Badarinarayan, Nandini, Jakobsdottir, Johanna, Hamilton-Nelson, Kara L., Moreno-Grau, Sonia, Olaso, Robert, Raybould, Rachel, Chen, Yuning, Kuzma, Amanda B., Hiltunen, Mikko, Morgan, Taniesha, Ahmad, Shahzad, Vardarajan, Badri N., Epelbaum, Jacques, Hoffmann, Per, Boada, Merce, Beecham, Gary W., Garnier, Jean-Guillaume, Harold, Denise, Fitzpatrick, Annette L., Valladares, Otto, Moutet, Marie-Laure, Gerrish, Amy, Smith, Albert V., Qu, Liming, Bacq, Delphine, Denning, Nicola, Jian, Xueqiu, Zhao, Yi, Del Zompo, Maria, Fox, Nick C., Choi, Seung-Hoan, Mateo, Ignacio, Hughes, Joseph T., Adams, Hieab H., Malamon, John, Sanchez-Garcia, Florentino, Patel, Yogen, Brody, Jennifer A., Dombroski, Beth A., Naranjo, Maria Candida Deniz, Daniilidou, Makrina, Eiriksdottir, Gudny, Mukherjee, Shubhabrata, Wallon, David, Uphill, James, Aspelund, Thor, Cantwell, Laura B., Garzia, Fabienne, Galimberti, Daniela, Hofer, Edith, Butkiewicz, Mariusz, Fin, Bertrand, Scarpini, Elio, Sarnowski, Chloe, Bush, Will S., Meslage, Stéphane, Kornhuber, Johannes, White, Charles C., Song, Yuenjoo, Barber, Robert C., Engelborghs, Sebastiaan, Sordon, Sabrina, Voijnovic, Dina, Adams, Perrie M., Vandenberghe, Rik, Mayhaus, Manuel, Cupples, L. Adrienne, Albert, Marilyn S., De Deyn, Peter P., Gu, Wei, Himali, Jayanadra J., Beekly, Duane, Squassina, Alessio, Hartmann, Annette M., Orellana, Adelina, Blacker, Deborah, Rodriguez-Rodriguez, Eloy, Lovestone, Simon, Garcia, Melissa E., Doody, Rachelle S., Munoz-Fernadez, Carmen, Sussams, Rebecca, Lin, Honghuang, Fairchild, Thomas J., Benito, Yolanda A., Holmes, Clive, Karamujić-Čomić, Hata, Frosch, Matthew P., Thonberg, Hakan, Maier, Wolfgang, Roshchupkin, Gennady, Ghetti, Bernardino, Giedraitis, Vilmantas, Kawalia, Amit, Li, Shuo, Huebinger, Ryan M., Kilander, Lena, Moebus, Susanne, Hernández, Isabel, Kamboh, M. Ilyas, Brundin, RoseMarie, Turton, James, Yang, Qiong, Katz, Mindy J., Concari, Letizia, Lord, Jenny, Beiser, Alexa S., Keene, C. Dirk, Helisalmi, Seppo, Kloszewska, Iwona, Kukull, Walter A., Koivisto, Anne Maria, Lynch, Aoibhinn, Tarraga, Lluís, Larson, Eric B., Haapasalo, Annakaisa, Lawlor, Brian, Mosley, Thomas H., Lipton, Richard B., Solfrizzi, Vincenzo, Gill, Michael, Longstreth, Jr, W. T., Montine, Thomas J., Frisardi, Vincenza, Diez-Fairen, Monica, Rivadeneira, Fernando, Petersen, Ronald C., Deramecourt, Vincent, Alvarez, Ignacio, Salani, Francesca, Ciaramella, Antonio, Boerwinkle, Eric, Reiman, Eric M., Fievet, Nathalie, Rotter, Jerome I., Reisch, Joan S., Hanon, Olivier, Cupidi, Chiara, Uitterlinden, A. G. Andre, Royall, Donald R., Dufouil, Carole, Maletta, Raffaele Giovanni, de Rojas, Itziar, Sano, Mary, Brice, Alexis, Cecchetti, Roberta, George-Hyslop, Peter St, Ritchie, Karen, Tsolaki, Magda, Tsuang, Debby W., Dubois, Bruno, Craig, David, Wu, Chuang-Kuo, Soininen, Hilkka, Avramidou, Despoina, Albin, Roger L., Fratiglioni, Laura, Germanou, Antonia, Apostolova, Liana G., Keller, Lina, Koutroumani, Maria, Arnold, Steven E., Panza, Francesco, Gkatzima, Olymbia, Asthana, Sanjay, Hannequin, Didier, Whitehead, Patrice, Atwood, Craig S., Caffarra, Paolo, Hampel, Harald, Quintela, Inés, Carracedo, Ángel, Lannfelt, Lars, Rubinsztein, David C., Barnes, Lisa L., Pasquier, Florence, Frölich, Lutz, Barral, Sandra, McGuinness, Bernadette, Beach, Thomas G., Johnston, Janet A., Becker, James T., Passmore, Peter, Bigio, Eileen H., Schott, Jonathan M., Bird, Thomas D., Warren, Jason D., Boeve, Bradley F., Lupton, Michelle K., Bowen, James D., Proitsi, Petra, Boxer, Adam, Powell, John F., Burke, James R., Kauwe, John S. K., Burns, Jeffrey M., Mancuso, Michelangelo, Buxbaum, Joseph D., Bonuccelli, Ubaldo, Cairns, Nigel J., McQuillin, Andrew, Cao, Chuanhai, Livingston, Gill, Carlson, Chris S., Bass, Nicholas J., Carlsson, Cynthia M., Hardy, John, Carney, Regina M., Bras, Jose, Carrasquillo, Minerva M., Guerreiro, Rita, Allen, Mariet, Chui, Helena C., Fisher, Elizabeth, Masullo, Carlo, Crocco, Elizabeth A., DeCarli, Charles, Bisceglio, Gina, Dick, Malcolm, Ma, Li, Duara, Ranjan, Graff-Radford, Neill R., Evans, Denis A., Hodges, Angela, Faber, Kelley M., Scherer, Martin, Fallon, Kenneth B., Riemenschneider, Matthias, Fardo, David W., Heun, Reinhard, Farlow, Martin R., Kölsch, Heike, Ferris, Steven, Leber, Markus, Foroud, Tatiana M., Heuser, Isabella, Galasko, Douglas R., Giegling, Ina, Gearing, Marla, Hüll, Michael, Geschwind, Daniel H., Gilbert, John R., Morris, John, Green, Robert C., Mayo, Kevin, Growdon, John H., Feulner, Thomas, Hamilton, Ronald L., Harrell, Lindy E., Drichel, Dmitriy, Honig, Lawrence S., Cushion, Thomas D., Huentelman, Matthew J., Hollingworth, Paul, Hulette, Christine M., Hyman, Bradley T., Marshall, Rachel, Jarvik, Gail P., Meggy, Alun, Abner, Erin, Menzies, Georgina E., Jin, Lee-Way, Leonenko, Ganna, Real, Luis M., Jun, Gyungah R., Baldwin, Clinton T., Grozeva, Detelina, Karydas, Anna, Russo, Giancarlo, Kaye, Jeffrey A., Kim, Ronald, Jessen, Frank, Kowall, Neil W., Vellas, Bruno, Kramer, Joel H., Vardy, Emma, LaFerla, Frank M., Jöckel, Karl-Heinz, Lah, James J., Dichgans, Martin, Leverenz, James B., Mann, David, Levey, Allan I., Pickering-Brown, Stuart, Lieberman, Andrew P., Klopp, Norman, Lunetta, Kathryn L., Wichmann, H-Erich, Lyketsos, Constantine G., Morgan, Kevin, Marson, Daniel C., Brown, Kristelle, Martiniuk, Frank, Medway, Christopher, Mash, Deborah C., Nöthen, Markus M., Masliah, Eliezer, Hooper, Nigel M., McCormick, Wayne C., Daniele, Antonio, McCurry, Susan M., Bayer, Anthony, McDavid, Andrew N., Gallacher, John, McKee, Ann C., van den Bussche, Hendrik, Mesulam, Marsel, Brayne, Carol, Miller, Bruce L., Riedel-Heller, Steffi, Miller, Carol A., Miller, Joshua W., Al-Chalabi, Ammar, Morris, John C., Shaw, Christopher E., Myers, Amanda J., Wiltfang, Jens, O’Bryant, Sid, Olichney, John M., Alvarez, Victoria, Parisi, Joseph E., Singleton, Andrew B., Paulson, Henry L., Collinge, John, Perry, William R., Mead, Simon, Peskind, Elaine, Cribbs, David H., Rossor, Martin, Pierce, Aimee, Ryan, Natalie S., Poon, Wayne W., Nacmias, Benedetta, Potter, Huntington, Sorbi, Sandro, Quinn, Joseph F., Sacchinelli, Eleonora, Raj, Ashok, Spalletta, Gianfranco, Raskind, Murray, Caltagirone, Carlo, Bossù, Paola, Orfei, Maria Donata, Reisberg, Barry, Clarke, Robert, Reitz, Christiane, Smith, A David, Ringman, John M., Warden, Donald, Roberson, Erik D., Wilcock, Gordon, Rogaeva, Ekaterina, Bruni, Amalia Cecilia, Rosen, Howard J., Gallo, Maura, Rosenberg, Roger N., Ben-Shlomo, Yoav, Sager, Mark A., Mecocci, Patrizia, Saykin, Andrew J., Pastor, Pau, Cuccaro, Michael L., Vance, Jeffery M., Schneider, Julie A., Schneider, Lori S., Slifer, Susan, Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tang, Mitchell, Tanzi, Rudolph E., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Wingo, Thomas S., Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Saba, Yasaman, Alzheimer Disease Genetics Consortium (ADGC), The European Alzheimer’s Disease Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES), Pilotto, Alberto, Bullido, Maria J., Peters, Oliver, Crane, Paul K., Bennett, David, Bosco, Paola, Coto, Eliecer, Boccardi, Virginia, De Jager, Phil L., Lleo, Alberto, Warner, Nick, Lopez, Oscar L., Ingelsson, Martin, Deloukas, Panagiotis, Cruchaga, Carlos, Graff, Caroline, Gwilliam, Rhian, Fornage, Myriam, Goate, Alison M., Sanchez-Juan, Pascual, Kehoe, Patrick G., Amin, Najaf, Ertekin-Taner, Nilifur, Berr, Claudine, Debette, Stéphanie, Love, Seth, Launer, Lenore J., Younkin, Steven G., Dartigues, Jean-Francois, Corcoran, Chris, Ikram, M. Arfan, Dickson, Dennis W., Nicolas, Gael, Campion, Dominique, Tschanz, JoAnn, Schmidt, Helena, Hakonarson, Hakon, Clarimon, Jordi, Munger, Ron, Schmidt, Reinhold, Farrer, Lindsay A., Van Broeckhoven, Christine, O’Donovan, Michael C., DeStefano, Anita L., Jones, Lesley, Haines, Jonathan L., Deleuze, Jean-Francois, Owen, Michael J., Gudnason, Vilmundur, Mayeux, Richard, Escott-Price, Valentina, Psaty, Bruce M., Ramirez, Alfredo, Wang, Li-San, Ruiz, Agustin, van Duijn, Cornelia M., Holmans, Peter A., Seshadri, Sudha, Williams, Julie, Amouyel, Phillippe, Schellenberg, Gerard D., Lambert, Jean-Charles, and Pericak-Vance, Margaret A.

Published
2019
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17. Induced pluripotent stem cell model revealed impaired neurovascular interaction in genetic small vessel disease Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.

Author

Wenjun Zhang, Xiangjun Zhao, Xuewei Qi, Kimber, Susan J., Hooper, Nigel M., and Tao Wang

Subjects
CEREBRAL small vessel diseases, INDUCED pluripotent stem cells, PLURIPOTENT stem cells, MOLECULAR pathology, LEUKOENCEPHALOPATHIES, TIGHT junctions, ARTERIAL diseases
Abstract

Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common genetic small vessel disease caused by variants in the NOTCH3 gene. Patients with CADASIL experience recurrent strokes, developing into cognitive defect and vascular dementia. CADASIL is a late-onset vascular condition, but migraine and brain MRI lesions appear in CADASIL patients as early as their teens and twenties, suggesting an abnormal neurovascular interaction at the neurovascular unit (NVU) where microvessels meet the brain parenchyma. Methods: To understand the molecular mechanisms of CADASIL, we established induced pluripotent stem cell (iPSC) models from CADASIL patients and differentiated the iPSCs into the major NVU cell types including brain microvascular endothelial-like cells (BMECs), vascular mural cells (MCs), astrocytes and cortical projection neurons. We then built an in vitro NVU model by co-culturing different neurovascular cell types in Transwells and evaluated the blood brain barrier (BBB) function by measuring transendothelial electrical resistance (TEER). Results: Results showed that, while the wild-type MCs, astrocytes and neurons could all independently and significantly enhance TEER of the iPSC-BMECs, such capability of MCs from iPSCs of CADASIL patients was significantly impaired. Additionally, the barrier function of the BMECs from CADASIL iPSCs was significantly decreased, accompanied with disorganized tight junctions in iPSC-BMECs, which could not be rescued by the wildtype MCs or sufficiently rescued by the wild-type astrocytes and neurons. Discussion: Our findings provide new insight into early disease pathologies on the neurovascular interaction and BBB function at the molecular and cellular levels for CADASIL, which helps inform future therapeutic development. [ABSTRACT FROM AUTHOR]

Published
2023
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18. Proteolysis of the low‐density lipoprotein receptor in hepatocytes is mediated by BMP1 but not by other astacin proteases.

Author

Kellett, Katherine A. B., Fisher, Kate, Aldworth, Harry, and Hooper, Nigel M.

Subjects
LIPOPROTEIN receptors, BONE morphogenetic proteins, LIVER cells, PROTEOLYSIS, LDL cholesterol, PROTEOLYTIC enzymes
Abstract

Bone morphogenetic protein 1 (BMP1), a member of the astacin family of zinc‐metalloproteases, proteolytically cleaves the low‐density lipoprotein receptor (LDLR) within its ligand‐binding domain, reducing the binding and cellular uptake of LDL‐cholesterol. Here, we aimed to determine whether astacin proteases other than BMP1 may also cleave LDLR. Although human hepatocytes express all six astacin proteases, including the meprins and mammalian tolloid, we found through pharmacological inhibition and genetic knockdown that only BMP1 contributed to the cleavage of LDLR in its ligand‐binding domain. We also found that the minimum amino acid change required to render mouse LDLR susceptible to cleavage by BMP1 is mutation at the P1′ and P2 positions of the cleavage site. When expressed in cells, the resulting humanised‐mouse LDLR internalised LDL‐cholesterol. This work provides insight into the biological mechanisms regulating LDLR function. [ABSTRACT FROM AUTHOR]

Published
2023
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20. Mendelian adult-onset leukodystrophy genes in Alzheimer's disease: critical influence of CSF1R and NOTCH3

Author

Passmore, Peter, Craig, David, Johnston, Janet, McGuinness, Bernadette, Todd, Stephen, Heun, Reinhard, Kölsch, Heike, Kehoe, Patrick G., Vardy, Emma R.L.C., Hooper, Nigel M., Mann, David M., Pickering-Brown, Stuart, Brown, Kristelle, Lowe, James, Morgan, Kevin, Smith, A. David, Wilcock, Gordon, Warden, Donald, Holmes, Clive, Sassi, Celeste, Nalls, Michael A., Ridge, Perry G., Gibbs, Jesse R., Lupton, Michelle K., Troakes, Claire, Lunnon, Katie, Al-Sarraj, Safa, Brown, Kristelle S., Medway, Christopher, Lord, Jenny, Turton, James, Bras, Jose, Blumenau, Sonja, Thielke, Mareike, Josties, Christa, Freyer, Dorette, Dietrich, Annette, Hammer, Monia, Baier, Michael, Dirnagl, Ulrich, Powell, John F., Kauwe, John S., Cruchaga, Carlos, Goate, Alison M., Singleton, Andrew B., Guerreiro, Rita, Hodges, Angela, and Hardy, John

Published
2018
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21. Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease

Author

Passmore, Peter, Craig, David, Johnston, Janet, McGuinness, Bernadette, Todd, Stephen, Heun, Reinhard, Kölsch, Heike, Kehoe, Patrick G., Vardy, Emma R.L.C., Hooper, Nigel M., Pickering-Brown, Stuart, Snowden, Julie, Richardson, Anna, Jones, Matthew, Neary, David, Harris, Jennifer, Lowe, James, Smith, A. David, Wilcock, Gordon, Warden, Donald, Holmes, Clive, Chaudhury, Sultan, Patel, Tulsi, Barber, Imelda S., Guetta-Baranes, Tamar, Brookes, Keeley J., Chappell, Sally, Turton, James, Guerreiro, Rita, Bras, Jose, Hernandez, Dena, Singleton, Andrew, Hardy, John, Mann, David, and Morgan, Kevin

Published
2018
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24. Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array

Author

Passmore, Peter, Craig, David, Johnston, Janet, McGuinness, Bernadette, Todd, Stephen, Heun, Reinhard, Kölsch, Heike, Kehoe, Patrick G., Vardy, Emma R.L.C., Hooper, Nigel M., Pickering-Brown, Stuart, Snowden, Julie, Richardson, Anna, Jones, Matthew, Neary, David, Harris, Jennifer, Lowe, James, Smith, A. David, Wilcock, Gordon, Warden, Donald, Holmes, Clive, Barber, Imelda S., Braae, Anne, Clement, Naomi, Patel, Tulsi, Guetta-Baranes, Tamar, Brookes, Keeley, Medway, Christopher, Chappell, Sally, Guerreiro, Rita, Bras, Jose, Hernandez, Dena, Singleton, Andrew, Hardy, John, Mann, David M., and Morgan, Kevin

Published
2017
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25. ABCA7 p.G215S as potential protective factor for Alzheimer's disease

Author

Passmore, Peter, Craig, David, Johnston, Janet, McGuinness, Bernadette, Todd, Stephen, Heun, Reinhard, Kölsch, Heike, Kehoe, Patrick G., Vardy, Emma R.L.C., Hooper, Nigel M., Mann, David M., Pickering-Brown, Stuart, Brown, Kristelle, Lowe, James, Morgan, Kevin, Smith, A. David, Wilcock, Gordon, Warden, Donald, Holmes, Clive, Sassi, Celeste, Nalls, Michael A., Ridge, Perry G., Gibbs, Jesse R., Ding, Jinhui, Lupton, Michelle K., Troakes, Claire, Lunnon, Katie, Al-Sarraj, Safa, Brown, Kristelle S., Medway, Christopher, Clement, Naomi, Lord, Jenny, Turton, James, Bras, Jose, Almeida, Maria R., Holstege, Henne, Louwersheimer, Eva, van der Flier, Wiesje M., Scheltens, Philip, Van Swieten, John C., Santana, Isabel, Oliveira, Catarina, Powell, John F., Kauwe, John S., Cruchaga, Carlos, Goate, Alison M., Singleton, Andrew B., Guerreiro, Rita, and Hardy, John

Published
2016
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27. Screening exons 16 and 17 of the amyloid precursor protein gene in sporadic early-onset Alzheimer's disease

Author

Passmore, Peter, Craig, David, Johnston, Janet, McGuinness, Bernadette, Todd, Stephen, Heun, Reinhard, Kölsch, Heike, Kehoe, Patrick G., Vardy, Emma R.L.C., Hooper, Nigel M., Pickering-Brown, Stuart, Snowden, Julie, Richardson, Anna, Jones, Matt, Neary, David, Harris, Jenny, Medway, Christopher, Lowe, James, Smith, A. David, Wilcock, Gordon, Warden, Donald, Holmes, Clive, Barber, Imelda S., García-Cárdenas, Jennyfer M., Sakdapanichkul, Chidchanok, Deacon, Christopher, Zapata Erazo, Gabriela, Guerreiro, Rita, Bras, Jose, Hernandez, Dena, Singleton, Andrew, Guetta-Baranes, Tamar, Braae, Anne, Clement, Naomi, Patel, Tulsi, Brookes, Keeley, Chappell, Sally, Mann, David M., and Morgan, Kevin

Published
2016
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28. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease

Author

Cruchaga, Carlos, Karch, Celeste M., Jin, Sheng Chih, Benitez, Bruno A., Cai, Yefei, Guerreiro, Rita, Harari, Oscar, Norton, Joanne, Budde, John, Bertelsen, Sarah, Jeng, Amanda T., Cooper, Breanna, Skorupa, Tara, Carrell, David, Levitch, Denise, Hsu, Simon, Choi, Jiyoon, Ryten, Mina, Trabzuni, Daniah, Weale, Michael E., Ramasamy, Adaikalavan, Smith, Colin, Sassi, Celeste, Bras, Jose, Gibbs, Raphael J., Hernandez, Dena G., Lupton, Michelle K., Powell, John, Forabosco, Paola, Ridge, Perry G., Corcoran, Christopher D., Tschanz, JoAnn T., Norton, Maria C., Munger, Ronald G., Schmutz, Cameron, Leary, Maegan, Demirci, Yesim F., Bamne, Mikhil N., Wang, Xingbin, Lopez, Oscar L., Ganguli, Mary, Medway, Christopher, Turton, James, Lord, Jenny, Braae, Anne, Barber, Imelda, Passmore, Peter, Craig, David, Johnston, Janet, McGuinness, Bernadette, Todd, Stephen, Heun, Reinhard, Kölsch, Heike, Kehoe, Patrick G., Hooper, Nigel M., Vardy, Emma R.L.C., Mann, David M., Pickering-Brown, Stuart, Brown, Kristelle, Kalsheker, Noor, Lowe, James, Morgan, Kevin, Smith, David A., Wilcock, Gordon, Warden, Donald, Holmes, Clive, Pastor, Pau, Lorenzo-Betancor, Oswaldo, Brkanac, Zoran, Scott, Erick, Topol, Eric, Rogaeva, Ekaterina, Singleton, Andrew B., Hardy, John, Kamboh, Ilyas M., St George-Hyslop, Peter, Cairns, Nigel, Morris, John C., Kauwe, John S. K., and Goate, Alison M.

Published
2014
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29. A new take on prions: preventing Alzheimer's disease

Author

Hooper, Nigel M. and Turner, Anthony J.

Subjects
Alzheimer's disease -- Prevention, Prions -- Properties, Prions -- Influence, Amyloid beta-protein -- Properties, Amyloid beta-protein -- Control, Biological sciences, Chemistry
Abstract

Alzheimer's disease is a major neurodegenerative disease of the brain, the incidence of which increases dramatically in old age. Currently, no drugs are available to halt or slow the progression of this disease, which poses an ever-expanding burden on health services, families and society. The prion protein has become infamous owing to its role as the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans. However, our view of the prion protein as an unwanted, harmful entity has been challenged recently. New data indicate that the normal cellular form of the prion protein might have a crucial role in suppressing the production of the amyIoid-[beta] peptide, the neurotoxic molecule involved in the pathogenesis of Alzheimer's disease.

Published
2008

31. Cellular prion protein regulates [beta]-secretase cleavage of the Alzheimer's amyloid precursor protein

Author

Parkin, Edward T., Watt, Nicole T., Hussain, Ishrut, Eckman, Elizabeth A., Eckman, Christopher B., Manson, Jean C., Baybutt, Herbert N., Turner, Anthony J., and Hooper, Nigel M.

Subjects
Alzheimer's disease -- Causes of, Alzheimer's disease -- Chemical properties, Alzheimer's disease -- Physiological aspects, Amyloid beta-protein -- Health aspects, Amyloid beta-protein -- Physiological aspects, Prions -- Chemical properties, Prions -- Physiological aspects, Science and technology
Abstract

Proteolytic processing of the amyloid precursor protein (APP) by [beta]-secretase, [beta]-site APP cleaving enzyme (BACE1), is the initial step in the production of the amyloid [beta] (A[beta]) peptide, which is involved in the pathogenesis of Alzheimer's disease. The normal cellular function of the prion protein (Pr[P.sup.C]), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans, remains enigmatic. Because both APP and Pr[P.sup.C] are subject to proteolytic processing by the same zinc metal-loproteases, we tested the involvement of Pr[P.sup.C] in the proteolytic processing of APP. Cellular overexpression of Pr[P.sup.C] inhibited the [beta]-secretase cleavage of APP and reduced A[beta] formation. Conversely, depletion of Pr[P.sup.C] in mouse N2a cells by siRNA led to an increase in A[beta] peptides secreted into the medium. In the brains of PrP knockout mice and in the brains from two strains of scrapie-infected mice, A[beta] levels were significantly increased. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases failed to inhibit the [beta]-secretase cleavage of APP. Using constructs of PrP, we show that this regulatory effect of Pr[P.sup.C] on the [beta]-secretase cleavage of APP required the localization of Pr[P.sup.C] to cholesterol-rich lipid rafts and was mediated by the N-terminal polybasic region of Pr[P.sup.C] via interaction with glycosaminoglycans. In conclusion, this is a mechanism by which the cellular production of the neurotoxic A[beta] is regulated by Pr[P.sup.C] and may have implications for both Alzheimer's and prion diseases. lipid raft | proteolysis | scrapie | glycosaminoglycan

Published
2007

33. Isolation and characterization of glycosylphosphatidylinositol-anchored peptides by hydrophilic interaction chromatography and MALDI tandem mass spectrometry

Author

Omaetxebarria, Miren J., Hagglund, Per, Elortza, Felix, Hooper, Nigel M., Arizmendi, Jesus M., and Jensen, Ole N.

Subjects
Mass spectrometry -- Usage, Ionization -- Analysis, Glycoproteins -- Structure, Glycoproteins -- Properties, Chemistry
Abstract

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are posttranslationally processed proteins that become tethered to the extracellular leaflet of the plasma membrane via a C-terminal glycan-like moiety. Since the first GPI-AP was described in the 1970s, more than 500 GPI-APs have been reported in a range of species, including plants, microbes, and mammals. GPI-APs are probably involved in cell signaling, cell recognition, and cell remodeling processes, and they may potentially serve as cell surface antigens or vaccine targets in pathogenic microorganisms or transformed mammalian cells. Due to the structural complexity and physicochemical properties of GPI-APs, their identification and structural characterization is a demanding analytical task. Here, we report a simple, fast and sensitive method for isolation and structural analysis of GPI-anchors using a combination of hydrophilic interaction liquid chromatography and matrix-assisted laser desorption/ionization (MALDI) quadrupole time-of-flight tandem mass spectrometry. This method allowed analysis of GPI peptides derived from low picomole levels of the porcine kidney membrane dipeptidase. Furthermore, it allowed unambiguous assignment of the omega site via amino acid sequencing of the modified peptides. GPI-anchor-specific diagnostic ions were observed by MALDI-MS/MS at m/z 162, 286, 422, and 447, corresponding to glucosamine, mannose ethanolamine phosphate, glucosamine inositol phosphate, and mannose ethanolamine phosphate glucosamine, respectively. Thus, the methodology described herein may enable sensitive and specific detection of GPI-anchored peptides in large-scale proteomic studies of plasma membrane proteins.

Published
2006

36. Exclusively targeting [beta]-secretase to lipid rafts by GPI-anchor addition up-regulates [beta]-site processing of the amyloid precursor protein

Author

Cordy, Joanna M., Hussain, Ishrut, Dingwall, Colin, Hooper, Nigel M., and Turner, Anthony J.

Subjects
Lipids -- Influence, Lipids -- Physiological aspects, Aging -- Physiological aspects, Amyloid beta-protein -- Physiological aspects, Science and technology
Abstract

[beta]-Secretase (BACE, Asp-2) is a transmembrane aspartic proteinase responsible for cleaving the amyloid precursor protein (APP) to generate the soluble ectodomain sAPP[beta] and its C-terminal fragment CTF[betha]. CTF[betha] is subsequently cleaved by [gamma]-secretase to produce the neurotoxic/synaptotoxic amyloid-[beta] peptide (A[beta]) that accumulates in Alzheimer's disease. Indirect evidence has suggested that amyloidogenic APP processing may preferentially occur in lipid rafts. Here, we show that relatively little wild-type BACE is found in rafts prepared from a human neuroblastoma cell line (SH-SY5Y) by using Triton X-100 as detergent. To investigate further the significance of lipid rafts in APP processing, a glycosylphosphati-dylinositol (GPI) anchor has been added to BACE, replacing the transmembrane and C-terminal domains. The GPI anchor targets the enzyme exclusively to lipid raft domains. Expression of GPIBACE substantially up-regulates the secretion of both sAPP[betha] and amyloid-[betha] peptide over levels observed from cells overexpressing wild-type BACE. This effect was reversed when the lipid rafts were disrupted by depleting cellular cholesterol levels. These results suggest that processing of APP to the amyloid-[betha] peptide occurs predominantly in lipid rafts and that BACE is the rate-limiting enzyme in this process. The processing of the AP[P.sub.695] isoform by GPI-BACE was up-regulated 20-fold compared with wild-type BACE, whereas only a 2-fold increase in the processing of AP[P.sub.751/770] was seen, implying a differential compartmentation of the APP isoforms. Changes in the local membrane environment during aging may facilitate the cosegregation of APP and BACE leading to increased [beta]-amyloid production.

Published
2003

37. The prion protein and neuronal zinc homeostasis

Author

Watt, Nicole T. and Hooper, Nigel M.

Subjects
Prion diseases -- Causes of, Endocytosis -- Analysis, Zinc -- Physiological aspects, Copper -- Physiological aspects, Peptides -- Physiological aspects, Proteins -- Physiological aspects, Prions -- Physiological aspects, Biochemistry -- Research, Biological sciences, Chemistry
Abstract

Although the prion protein (PrP) is known to be the causative agent of the neurodegenerative transmissible spongiform encephalopathies, its normal cellular function remains elusive. Octapeptide repeats in the N terminus of PrP bind metal ions and are required for the endocytosis of PrP upon exposure of cells to copper or zinc. As the concentration of zinc in the extracellular spaces of the brain is higher than that for copper, we put forward the hypothesis that PrP is involved in neuronal zinc homeostasis; PrP might be involved in transport of zinc into the cell or might act as a zinc sensor. In prion disease, when the protein undergoes a conformational change to the infectious form, this function of PrP in zinc homeostasis might be compromised.

Published
2003

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