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1. LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry.

Author

Katsumata, Yuriko, Fardo, David W, Shade, Lincoln MP, Bowen, James D, Crane, Paul K, Jarvik, Gail P, Keene, C Dirk, Larson, Eric B, McCormick, Wayne C, McCurry, Susan M, Mukherjee, Shubhabrata, Kowall, Neil W, McKee, Ann C, Honig, Robert A, Lawrence, S, Vonsattel, Jean Paul, Williamson, Jennifer, Small, Scott, Burke, James R, Hulette, Christine M, Welsh-Bohmer, Kathleen A, Gearing, Marla, Lah, James J, Levey, Allan I, Wingo, Thomas S, Apostolova, Liana G, Farlow, Martin R, Ghetti, Bernardino, Saykin, Andrew J, Spina, Salvatore, Albert, Marilyn S, Lyketsos, Constantine G, Troncoso, Juan C, Frosch, Matthew P, Green, Robert C, Growdon, John H, Hyman, Bradley T, Tanzi, Rudolph E, Potter, Huntington, Dickson, Dennis W, Ertekin-Taner, Nilufer, Graff-Radford, Neill R, Parisi, Joseph E, Petersen, Ronald C, Duara, Ranjan, Buxbaum, Joseph D, Goate, Alison M, Sano, Mary, Masurkar, Arjun V, Wisniewski, Thomas, Bigio, Eileen H, Mesulam, Marsel, Weintraub, Sandra, Vassar, Robert, Kaye, Jeffrey A, Quinn, Joseph F, Woltjer, Randall L, Barnes, Lisa L, Bennett, David A, Schneider, Julie A, Yu, Lei, Henderson, Victor, Fallon, Kenneth B, Harrell, Lindy E, Marson, Daniel C, Roberson, Erik D, DeCarli, Charles, Jin, Lee-Way, Olichney, John M, Kim, Ronald, LaFerla, Frank M, Monuki, Edwin, Head, Elizabeth, Sultzer, David, Geschwind, Daniel H, Vinters, Harry V, Chesselet, Marie-Francoise, Galasko, Douglas R, Brewer, James B, Boxer, Adam, Karydas, Anna, Kramer, Joel H, Miller, Bruce L, Rosen, Howard J, Seeley, William W, Burns, Jeffrey M, Swerdlow, Russell H, Abner, Erin, Van Eldik, Linda J, Albin, Roger L, Lieberman, Andrew P, Paulson, Henry L, Arnold, Steven E, Trojanowski, John Q, Van Deerlin, Vivianna M, Hamilton, Ronald L, Kamboh, M Ilyas, Lopez, Oscar L, and Becker, James T

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Aging, Prevention, Neurodegenerative, Acquired Cognitive Impairment, Alzheimer's Disease, Dementia, Minority Health, Health Disparities, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Genetics, 2.1 Biological and endogenous factors, Humans, Alleles, Polymorphism, Single Nucleotide, Alzheimer Disease, TDP-43 Proteinopathies, Progranulins, Membrane Proteins, Nerve Tissue Proteins, Sulfonylurea Receptors, Alzheimer’s Disease Genetics Consortium, KCNMB2, Diversity, Epidemiology, FTLD, Genome-Wide Association Studies, KATP, Neurology & Neurosurgery, Clinical sciences
Abstract

Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

Published
2023

2. The status of digital pathology and associated infrastructure within Alzheimer’s Disease Centers

Author

Scalco, Rebeca, Hamsafar, Yamah, White, Charles L, Schneider, Julie A, Reichard, Robert Ross, Prokop, Stefan, Perrin, Richard J, Nelson, Peter T, Mooney, Sean, Lieberman, Andrew P, Kukull, Walter A, Kofler, Julia, Keene, Christopher Dirk, Kapasi, Alifiya, Irwin, David J, Gutman, David A, Flanagan, Margaret E, Crary, John F, Chan, Kwun C, Murray, Melissa E, and Dugger, Brittany N

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Dementia, Machine Learning and Artificial Intelligence, Aging, Brain Disorders, Acquired Cognitive Impairment, Neurodegenerative, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Industry, Innovation and Infrastructure, Humans, Alzheimer Disease, Workflow, Machine Learning, Surveys and Questionnaires, Alzheimer disease, Computational pathology, Deep Learning, Digital pathology, Quantitative pathology, Slide scanner, Neurology & Neurosurgery, Clinical sciences
Abstract

Digital pathology (DP) has transformative potential, especially for Alzheimer disease and related disorders. However, infrastructure barriers may limit adoption. To provide benchmarks and insights into implementation barriers, a survey was conducted in 2019 within National Institutes of Health's Alzheimer's Disease Centers (ADCs). Questions covered infrastructure, funding sources, and data management related to digital pathology. Of the 35 ADCs to which the survey was sent, 33 responded. Most respondents (81%) stated that their ADC had digital slide scanner access, with the most frequent brand being Aperio/Leica (62.9%). Approximately a third of respondents stated there were fees to utilize the scanner. For DP and machine learning (ML) resources, 41% of respondents stated none was supported by their ADC. For scanner purchasing and operations, 50% of respondents stated they received institutional support. Some were unsure of the file size of scanned digital images (37%) and total amount of storage space files occupied (50%). Most (76%) were aware of other departments at their institution working with ML; a similar (76%) percentage were unaware of multiuniversity or industry partnerships. These results demonstrate many ADCs have access to a digital slide scanner; additional investigations are needed to further understand hurdles to implement DP and ML workflows.

Published
2023

4. Human SIRT5 variants with reduced stability and activity do not cause neuropathology in mice

Author

Yuan, Taolin, Kumar, Surinder, Skinner, Mary E., Victor-Joseph, Ryan, Abuaita, Majd, Keijer, Jaap, Zhang, Jessica, Kunkel, Thaddeus J., Liu, Yanghan, Petrunak, Elyse M., Saunders, Thomas L., Lieberman, Andrew P., Stuckey, Jeanne A., Neamati, Nouri, Al-Murshedi, Fathiya, Alfadhel, Majid, Spelbrink, Johannes N., Rodenburg, Richard, de Boer, Vincent C.J., and Lombard, David B.

Published
2024
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6. Defective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca2+ accumulation in spinobulbar muscular atrophy skeletal muscle

Author

Marchioretti, Caterina, Zanetti, Giulia, Pirazzini, Marco, Gherardi, Gaia, Nogara, Leonardo, Andreotti, Roberta, Martini, Paolo, Marcucci, Lorenzo, Canato, Marta, Nath, Samir R., Zuccaro, Emanuela, Chivet, Mathilde, Mammucari, Cristina, Pacifici, Marco, Raffaello, Anna, Rizzuto, Rosario, Mattarei, Andrea, Desbats, Maria A., Salviati, Leonardo, Megighian, Aram, Sorarù, Gianni, Pegoraro, Elena, Belluzzi, Elisa, Pozzuoli, Assunta, Biz, Carlo, Ruggieri, Pietro, Romualdi, Chiara, Lieberman, Andrew P., Babu, Gopal J., Sandri, Marco, Blaauw, Bert, Basso, Manuela, and Pennuto, Maria

Published
2023
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7. Bicalutamide and Trehalose Ameliorate Spinal and Bulbar Muscular Atrophy Pathology in Mice

Author

Galbiati, Mariarita, Meroni, Marco, Boido, Marina, Cescon, Matilde, Rusmini, Paola, Crippa, Valeria, Cristofani, Riccardo, Piccolella, Margherita, Ferrari, Veronica, Tedesco, Barbara, Casarotto, Elena, Chierichetti, Marta, Cozzi, Marta, Mina, Francesco, Cicardi, Maria Elena, Pedretti, Silvia, Mitro, Nico, Caretto, Anna, Risè, Patrizia, Sala, Angelo, Lieberman, Andrew P., Bonaldo, Paolo, Pennuto, Maria, Vercelli, Alessandro, and Poletti, Angelo

Published
2023
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9. Niemann-Pick C1 protein regulates platelet membrane–associated calcium ion signaling in thrombo-occlusive diseases in mice

Author

Manke, Mailin-Christin, Roslan, Anna, Walker, Britta, Münzer, Patrick, Kollotzek, Ferdinand, Peng, Bing, Mencl, Stine, Coman, Cristina, Szepanowski, Rebecca D., Schulze, Harald, Lieberman, Andrew P., Lang, Florian, Gawaz, Meinrad, Kleinschnitz, Christoph, Lukowski, Robert, Ahrends, Robert, Bobe, Régis, and Borst, Oliver

Published
2023
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10. Author Correction: Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.

Author

Eftekharzadeh, Bahareh, Banduseela, Varuna C, Chiesa, Giulio, Martínez-Cristóbal, Paula, Rauch, Jennifer N, Nath, Samir R, Schwarz, Daniel MC, Shao, Hao, Marin-Argany, Marta, Di Sanza, Claudio, Giorgetti, Elisa, Yu, Zhigang, Pierattelli, Roberta, Felli, Isabella C, Brun-Heath, Isabelle, García, Jesús, Nebreda, Ángel R, Gestwicki, Jason E, Lieberman, Andrew P, and Salvatella, Xavier

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019

11. Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.

Author

Eftekharzadeh, Bahareh, Banduseela, Varuna C, Chiesa, Giulio, Martínez-Cristóbal, Paula, Rauch, Jennifer N, Nath, Samir R, Schwarz, Daniel MC, Shao, Hao, Marin-Argany, Marta, Di Sanza, Claudio, Giorgetti, Elisa, Yu, Zhigang, Pierattelli, Roberta, Felli, Isabella C, Brun-Heath, Isabelle, García, Jesús, Nebreda, Ángel R, Gestwicki, Jason E, Lieberman, Andrew P, and Salvatella, Xavier

Subjects
Animals, Mice, Transgenic, Humans, Mice, Receptors, Androgen, Androgens, Ligands, Nuclear Magnetic Resonance, Biomolecular, Solubility, Male, HSP70 Heat-Shock Proteins, HSP40 Heat-Shock Proteins, Protein Multimerization, Gene Knock-In Techniques, HEK293 Cells, Protein Aggregates, Protein Domains, Transgenic, Nuclear Magnetic Resonance, Biomolecular, Receptors, Androgen
Abstract

Molecular chaperones such as Hsp40 and Hsp70 hold the androgen receptor (AR) in an inactive conformation. They are released in the presence of androgens, enabling transactivation and causing the receptor to become aggregation-prone. Here we show that these molecular chaperones recognize a region of the AR N-terminal domain (NTD), including a FQNLF motif, that interacts with the AR ligand-binding domain (LBD) upon activation. This suggests that competition between molecular chaperones and the LBD for the FQNLF motif regulates AR activation. We also show that, while the free NTD oligomerizes, binding to Hsp70 increases its solubility. Stabilizing the NTD-Hsp70 interaction with small molecules reduces AR aggregation and promotes its degradation in cellular and mouse models of the neuromuscular disorder spinal bulbar muscular atrophy. These results help resolve the mechanisms by which molecular chaperones regulate the balance between AR aggregation, activation and quality control.

Published
2019

12. Analysis of shared heritability in common disorders of the brain

Author

Consortium, The Brainstorm, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K, Walters, Raymond K, Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J, Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A, Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H, Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-François, Duron, Emmanuelle, Vardarajan, Badri N, Reitz, Christiane, Goate, Alison M, Huentelman, Matthew J, Kamboh, M Ilyas, Larson, Eric B, Rogaeva, Ekaterina, St George-Hyslop, Peter, Hakonarson, Hakon, Kukull, Walter A, Farrer, Lindsay A, Barnes, Lisa L, Beach, Thomas G, Demirci, F Yesim, Head, Elizabeth, Hulette, Christine M, Jicha, Gregory A, Kauwe, John SK, Kaye, Jeffrey A, Leverenz, James B, Levey, Allan I, Lieberman, Andrew P, Pankratz, Vernon S, Poon, Wayne W, Quinn, Joseph F, Saykin, Andrew J, Schneider, Lon S, Smith, Amanda G, Sonnen, Joshua A, Stern, Robert A, Van Deerlin, Vivianna M, Van Eldik, Linda J, Harold, Denise, Russo, Giancarlo, Rubinsztein, David C, Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C, Hampel, Harald, Owen, Michael J, Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M, Schott, Jonathan M, Rossor, Martin, Lupton, Michelle K, Hoffmann, Per, Kornhuber, Johannes, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C, Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, van der Lee, Sven J, De Jager, Philip L, Geschwind, Daniel H, Riemenschneider, Matthias, Riedel-Heller, Steffi, Rotter, Jerome I, Ransmayr, Gerhard, Hyman, Bradley T, Cruchaga, Carlos, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, and Cuenca-Leon, Ester

Subjects
Biological Sciences, Genetics, Biological Psychology, Health Sciences, Psychology, Human Genome, Brain Disorders, Neurosciences, Mental Health, Mental Illness, Clinical Research, 2.1 Biological and endogenous factors, Neurological, Mental health, Brain Diseases, Genetic Variation, Genome-Wide Association Study, Humans, Mental Disorders, Phenotype, Quantitative Trait, Heritable, Risk Factors, Brainstorm Consortium, General Science & Technology
Abstract

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Published
2018

13. Analysis of shared heritability in common disorders of the brain.

Author

Brainstorm Consortium, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K, Walters, Raymond K, Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J, Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A, Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H, Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-François, Duron, Emmanuelle, Vardarajan, Badri N, Reitz, Christiane, Goate, Alison M, Huentelman, Matthew J, Kamboh, M Ilyas, Larson, Eric B, Rogaeva, Ekaterina, St George-Hyslop, Peter, Hakonarson, Hakon, Kukull, Walter A, Farrer, Lindsay A, Barnes, Lisa L, Beach, Thomas G, Demirci, F Yesim, Head, Elizabeth, Hulette, Christine M, Jicha, Gregory A, Kauwe, John SK, Kaye, Jeffrey A, Leverenz, James B, Levey, Allan I, Lieberman, Andrew P, Pankratz, Vernon S, Poon, Wayne W, Quinn, Joseph F, Saykin, Andrew J, Schneider, Lon S, Smith, Amanda G, Sonnen, Joshua A, Stern, Robert A, Van Deerlin, Vivianna M, Van Eldik, Linda J, Harold, Denise, Russo, Giancarlo, Rubinsztein, David C, Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C, Hampel, Harald, Owen, Michael J, Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M, Rossor, Martin, Lupton, Michelle K, Hoffmann, Per, Kornhuber, Johannes, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C, Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, van der Lee, Sven J, De Jager, Philip L, Geschwind, Daniel H, Riemenschneider, Matthias, Riedel-Heller, Steffi, Rotter, Jerome I, Ransmayr, Gerhard, Hyman, Bradley T, Cruchaga, Carlos, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, and Furlotte, Nicholas

Subjects
Brainstorm Consortium, Humans, Brain Diseases, Risk Factors, Mental Disorders, Quantitative Trait, Heritable, Phenotype, Genetic Variation, Genome-Wide Association Study, Clinical Research, Neurosciences, Rare Diseases, Human Genome, Brain Disorders, Genetics, Mental Health, 2.1 Biological and endogenous factors, Mental health, Neurological, General Science & Technology
Abstract

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Published
2018

23. Targeting Hsp90/Hsp70-Based Protein Quality Control for Treatment of Adult Onset Neurodegenerative Diseases

Author

Pratt, William B, Gestwicki, Jason E, Osawa, Yoichi, and Lieberman, Andrew P

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Dementia, Brain Disorders, Aging, Huntington's Disease, Neurosciences, Acquired Cognitive Impairment, Rare Diseases, Biotechnology, Neurodegenerative, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Neurological, Adult, Age of Onset, Animals, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, Humans, Nervous System, Neurodegenerative Diseases, Neuroprotective Agents, Proteasome Endopeptidase Complex, Protein Denaturation, Protein Folding, Protein Stability, Signal Transduction, Ubiquitin-Protein Ligases, Ubiquitination, neurodegeneration, protein aggregation, ubiquitination, CHIP, proteasome, Biological Sciences, Medical and Health Sciences, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences
Abstract

Currently available therapies for adult onset neurodegenerative diseases provide symptomatic relief but do not modify disease progression. Here we explore a new neuroprotective approach based on drugs targeting chaperone-directed protein quality control. Critical target proteins that unfold and aggregate in these diseases, such as the polyglutamine androgen receptor in spinal and bulbar muscular atrophy, huntingtin in Huntington's disease, α-synuclein in Parkinson's disease, and tau in Alzheimer's disease, are client proteins of heat shock protein 90 (Hsp90), and their turnover is regulated by the protein quality control function of the Hsp90/Hsp70-based chaperone machinery. Hsp90 and Hsp70 have opposing effects on client protein stability in protein quality control; Hsp90 stabilizes the clients and inhibits their ubiquitination, whereas Hsp70 promotes ubiquitination dependent on CHIP (C terminus of Hsc70-interacting protein) and proteasomal degradation. We discuss how drugs that modulate proteostasis by inhibiting Hsp90 function or promoting Hsp70 function enhance the degradation of the critical aggregating proteins and ameliorate toxic symptoms in cell and animal disease models.

Published
2015

24. A model in which heat shock protein 90 targets protein-folding clefts: Rationale for a new approach to neuroprotective treatment of protein folding diseases

Author

Pratt, William B, Morishima, Yoshihiro, Gestwicki, Jason E, Lieberman, Andrew P, and Osawa, Yoichi

Subjects
Biochemistry and Cell Biology, Biological Sciences, Acquired Cognitive Impairment, Neurodegenerative, Alzheimer's Disease, Brain Disorders, Dementia, Orphan Drug, Rare Diseases, Aging, Huntington's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Neurological, HSP90 Heat-Shock Proteins, Humans, Huntingtin Protein, Nerve Tissue Proteins, Neuroprotective Agents, Protein Folding, Proteolysis, Proteostasis Deficiencies, Receptors, Neurotransmitter, Ubiquitination, alpha-Synuclein, tau Proteins, Proteostasis, neurodegeneration, heat shock protein 90, heat shock protein 70, ubiquitination, carboxyl-terminus of Hsc70-interacting protein, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Engineering
Abstract

In an EBM Minireview published in 2010, we proposed that the heat shock protein (Hsp)90/Hsp70-based chaperone machinery played a major role in determining the selection of proteins that have undergone oxidative or other toxic damage for ubiquitination and proteasomal degradation. The proposal was based on a model in which the Hsp90 chaperone machinery regulates signaling by modulating ligand-binding clefts. The model provides a framework for thinking about the development of neuroprotective therapies for protein-folding diseases like Alzheimer's disease (AD), Parkinson's disease (PD), and the polyglutamine expansion disorders, such as Huntington's disease (HD) and spinal and bulbar muscular atrophy (SBMA). Major aberrant proteins that misfold and accumulate in these diseases are "client" proteins of the abundant and ubiquitous stress chaperone Hsp90. These Hsp90 client proteins include tau (AD), α-synuclein (PD), huntingtin (HD), and the expanded glutamine androgen receptor (polyQ AR) (SBMA). In this Minireview, we update our model in which Hsp90 acts on protein-folding clefts and show how it forms a rational basis for developing drugs that promote the targeted elimination of these aberrant proteins.

Published
2014

25. TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions.

Author

Gallagher, Michael D, Suh, Eunran, Grossman, Murray, Elman, Lauren, McCluskey, Leo, Van Swieten, John C, Al-Sarraj, Safa, Neumann, Manuela, Gelpi, Ellen, Ghetti, Bernardino, Rohrer, Jonathan D, Halliday, Glenda, Van Broeckhoven, Christine, Seilhean, Danielle, Shaw, Pamela J, Frosch, Matthew P, Alafuzoff, Irina, Antonell, Anna, Bogdanovic, Nenad, Brooks, William, Cairns, Nigel J, Cooper-Knock, Johnathan, Cotman, Carl, Cras, Patrick, Cruts, Marc, De Deyn, Peter P, DeCarli, Charles, Dobson-Stone, Carol, Engelborghs, Sebastiaan, Fox, Nick, Galasko, Douglas, Gearing, Marla, Gijselinck, Ilse, Grafman, Jordan, Hartikainen, Päivi, Hatanpaa, Kimmo J, Highley, J Robin, Hodges, John, Hulette, Christine, Ince, Paul G, Jin, Lee-Way, Kirby, Janine, Kofler, Julia, Kril, Jillian, Kwok, John BJ, Levey, Allan, Lieberman, Andrew, Llado, Albert, Martin, Jean-Jacques, Masliah, Eliezer, McDermott, Christopher J, McKee, Ann, McLean, Catriona, Mead, Simon, Miller, Carol A, Miller, Josh, Munoz, David G, Murrell, Jill, Paulson, Henry, Piguet, Olivier, Rossor, Martin, Sanchez-Valle, Raquel, Sano, Mary, Schneider, Julie, Silbert, Lisa C, Spina, Salvatore, van der Zee, Julie, Van Langenhove, Tim, Warren, Jason, Wharton, Stephen B, White, Charles L, Woltjer, Randall L, Trojanowski, John Q, Lee, Virginia MY, Van Deerlin, Vivianna, and Chen-Plotkin, Alice S

Subjects
Humans, Amyotrophic Lateral Sclerosis, Genetic Predisposition to Disease, Intercellular Signaling Peptides and Proteins, Proteins, Membrane Proteins, Nerve Tissue Proteins, Cohort Studies, Age Factors, Age of Onset, DNA Repeat Expansion, Genotype, Heterozygote, Polymorphism, Single Nucleotide, Alleles, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Frontotemporal Lobar Degeneration, C9orf72 Protein, Progranulins, Rare Diseases, Aging, Neurosciences, Alzheimer's Disease Related Dementias (ADRD), Brain Disorders, Neurodegenerative, Prevention, Genetics, Dementia, Frontotemporal Dementia (FTD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Aetiology, 2.1 Biological and endogenous factors, Neurological, TMEM106B, C9orf72, Frontotemporal dementia, Frontotemporal lobar degeneration, Amyotrophic lateral sclerosis, Genetic modifier, Clinical Sciences, Neurology & Neurosurgery
Abstract

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.

Published
2014

26. SIRT5 variants from patients with mitochondrial disease are associated with reduced SIRT5 stability and activity, but not with neuropathology

Author

Yuan, Taolin, primary, Kumar, Surinder, additional, Skinner, Mary E, additional, Victor-Joseph, Ryan, additional, Abuaita, Majd, additional, Keijer, Jaap, additional, Zhang, Jessica, additional, Kunkel, Thaddeus, additional, Liu, Yanghan, additional, Petrunak, Elyse, additional, Saunders, Thomas, additional, Lieberman, Andrew P., additional, Stuckey, Jeanne A., additional, Neamati, Nouri, additional, AlMurshedi, Fathiya, additional, Alfadhel, Majid, additional, Spelbrink, Johannes N, additional, Rodenburg, Richard, additional, de Boer, Vincent C.J., additional, and Lombard, David B, additional

Published
2023
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27. Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation.

Author

Wang, Adrienne, Miyata, Yoshinari, Klinedinst, Susan, Peng, Hwei-Ming, Chua, Jason, Komiyama, Tomoko, Li, Xiaokai, Morishima, Yoshihiro, Merry, Diane, Pratt, William, Osawa, Yoichi, Collins, Catherine, Lieberman, Andrew, and Gestwicki, Jason

Subjects
Animals, Dose-Response Relationship, Drug, Doxorubicin, Drosophila, Female, HEK293 Cells, HSP70 Heat-Shock Proteins, HeLa Cells, Humans, Inhibitory Concentration 50, Models, Chemical, Molecular Chaperones, Muscular Disorders, Atrophic, Neurotoxins, PC12 Cells, Peptides, Protein Structure, Tertiary, Proteins, Pyridines, Rats, Receptors, Androgen, Thiazoles, Ubiquitination
Abstract

We sought new strategies to reduce amounts of the polyglutamine androgen receptor (polyQ AR) and achieve benefits in models of spinobulbar muscular atrophy, a protein aggregation neurodegenerative disorder. Proteostasis of the polyQ AR is controlled by the heat shock protein 90 (Hsp90)- and Hsp70-based chaperone machinery, but mechanisms regulating the proteins turnover are incompletely understood. We demonstrate that overexpression of Hsp70 interacting protein (Hip), a co-chaperone that enhances binding of Hsp70 to its substrates, promotes client protein ubiquitination and polyQ AR clearance. Furthermore, we identify a small molecule that acts similarly to Hip by allosterically promoting Hsp70 binding to unfolded substrates. Like Hip, this synthetic co-chaperone enhances client protein ubiquitination and polyQ AR degradation. Both genetic and pharmacologic approaches targeting Hsp70 alleviate toxicity in a Drosophila model of spinobulbar muscular atrophy. These findings highlight the therapeutic potential of allosteric regulators of Hsp70 and provide new insights into the role of the chaperone machinery in protein quality control.

Published
2013

28. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

Author

Naj, Adam C, Jun, Gyungah, Beecham, Gary W, Wang, Li-San, Vardarajan, Badri Narayan, Buros, Jacqueline, Gallins, Paul J, Buxbaum, Joseph D, Jarvik, Gail P, Crane, Paul K, Larson, Eric B, Bird, Thomas D, Boeve, Bradley F, Graff-Radford, Neill R, De Jager, Philip L, Evans, Denis, Schneider, Julie A, Carrasquillo, Minerva M, Ertekin-Taner, Nilufer, Younkin, Steven G, Cruchaga, Carlos, Kauwe, John SK, Nowotny, Petra, Kramer, Patricia, Hardy, John, Huentelman, Matthew J, Myers, Amanda J, Barmada, Michael M, Demirci, F Yesim, Baldwin, Clinton T, Green, Robert C, Rogaeva, Ekaterina, George-Hyslop, Peter St, Arnold, Steven E, Barber, Robert, Beach, Thomas, Bigio, Eileen H, Bowen, James D, Boxer, Adam, Burke, James R, Cairns, Nigel J, Carlson, Chris S, Carney, Regina M, Carroll, Steven L, Chui, Helena C, Clark, David G, Corneveaux, Jason, Cotman, Carl W, Cummings, Jeffrey L, DeCarli, Charles, DeKosky, Steven T, Diaz-Arrastia, Ramon, Dick, Malcolm, Dickson, Dennis W, Ellis, William G, Faber, Kelley M, Fallon, Kenneth B, Farlow, Martin R, Ferris, Steven, Frosch, Matthew P, Galasko, Douglas R, Ganguli, Mary, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Gilman, Sid, Giordani, Bruno, Glass, Jonathan D, Growdon, John H, Hamilton, Ronald L, Harrell, Lindy E, Head, Elizabeth, Honig, Lawrence S, Hulette, Christine M, Hyman, Bradley T, Jicha, Gregory A, Jin, Lee-Way, Johnson, Nancy, Karlawish, Jason, Karydas, Anna, Kaye, Jeffrey A, Kim, Ronald, Koo, Edward H, Kowall, Neil W, Lah, James J, Levey, Allan I, Lieberman, Andrew P, Lopez, Oscar L, Mack, Wendy J, Marson, Daniel C, Martiniuk, Frank, Mash, Deborah C, Masliah, Eliezer, McCormick, Wayne C, McCurry, Susan M, McDavid, Andrew N, McKee, Ann C, Mesulam, Marsel, and Miller, Bruce L

Subjects
Biological Sciences, Genetics, Dementia, Neurodegenerative, Acquired Cognitive Impairment, Alzheimer's Disease, Human Genome, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Aging, 2.1 Biological and endogenous factors, Neurological, Adaptor Proteins, Signal Transducing, Age of Onset, Aged, Aged, 80 and over, Alzheimer Disease, Antigens, CD, Antigens, Differentiation, Myelomonocytic, Cohort Studies, Cytoskeletal Proteins, Databases, Genetic, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Membrane Proteins, Multigene Family, Polymorphism, Single Nucleotide, Receptor, EphA1, Sialic Acid Binding Ig-like Lectin 3, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Published
2011

29. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions

Author

Van Deerlin, Vivianna M, Sleiman, Patrick MA, Martinez-Lage, Maria, Chen-Plotkin, Alice, Wang, Li-San, Graff-Radford, Neill R, Dickson, Dennis W, Rademakers, Rosa, Boeve, Bradley F, Grossman, Murray, Arnold, Steven E, Mann, David MA, Pickering-Brown, Stuart M, Seelaar, Harro, Heutink, Peter, van Swieten, John C, Murrell, Jill R, Ghetti, Bernardino, Spina, Salvatore, Grafman, Jordan, Hodges, John, Spillantini, Maria Grazia, Gilman, Sid, Lieberman, Andrew P, Kaye, Jeffrey A, Woltjer, Randall L, Bigio, Eileen H, Mesulam, Marsel, al-Sarraj, Safa, Troakes, Claire, Rosenberg, Roger N, White, Charles L, Ferrer, Isidro, Lladó, Albert, Neumann, Manuela, Kretzschmar, Hans A, Hulette, Christine Marie, Welsh-Bohmer, Kathleen A, Miller, Bruce L, Alzualde, Ainhoa, de Munain, Adolfo Lopez, McKee, Ann C, Gearing, Marla, Levey, Allan I, Lah, James J, Hardy, John, Rohrer, Jonathan D, Lashley, Tammaryn, Mackenzie, Ian RA, Feldman, Howard H, Hamilton, Ronald L, Dekosky, Steven T, van der Zee, Julie, Kumar-Singh, Samir, Van Broeckhoven, Christine, Mayeux, Richard, Vonsattel, Jean Paul G, Troncoso, Juan C, Kril, Jillian J, Kwok, John BJ, Halliday, Glenda M, Bird, Thomas D, Ince, Paul G, Shaw, Pamela J, Cairns, Nigel J, Morris, John C, McLean, Catriona Ann, DeCarli, Charles, Ellis, William G, Freeman, Stefanie H, Frosch, Matthew P, Growdon, John H, Perl, Daniel P, Sano, Mary, Bennett, David A, Schneider, Julie A, Beach, Thomas G, Reiman, Eric M, Woodruff, Bryan K, Cummings, Jeffrey, Vinters, Harry V, Miller, Carol A, Chui, Helena C, Alafuzoff, Irina, Hartikainen, Päivi, Seilhean, Danielle, Galasko, Douglas, Masliah, Eliezer, Cotman, Carl W, Tuñón, M Teresa, Martínez, M Cristina Caballero, Munoz, David G, Carroll, Steven L, Marson, Daniel, Riederer, Peter F, Bogdanovic, Nenad, Schellenberg, Gerard D, Hakonarson, Hakon, Trojanowski, John Q, and Lee, Virginia M-Y

Subjects
Biological Sciences, Genetics, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Frontotemporal Dementia (FTD), Dementia, Aging, Brain Disorders, Neurodegenerative, Acquired Cognitive Impairment, Alzheimer's Disease Related Dementias (ADRD), Neurosciences, 2.1 Biological and endogenous factors, Case-Control Studies, Chromosomes, Human, Pair 7, DNA-Binding Proteins, Frontotemporal Lobar Degeneration, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Inclusion Bodies, Intercellular Signaling Peptides and Proteins, Linkage Disequilibrium, Membrane Proteins, Polymorphism, Single Nucleotide, Progranulins, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.

Published
2010

31. Combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: a phase 1, first-in-human trial

Author

Umemura, Yoshie, primary, Orringer, Daniel, additional, Junck, Larry, additional, Varela, Maria L, additional, West, Molly E J, additional, Faisal, Syed M, additional, Comba, Andrea, additional, Heth, Jason, additional, Sagher, Oren, additional, Leung, Denise, additional, Mammoser, Aaron, additional, Hervey-Jumper, Shawn, additional, Zamler, Daniel, additional, Yadav, Viveka N, additional, Dunn, Patrick, additional, Al-Holou, Wajd, additional, Hollon, Todd, additional, Kim, Michelle M, additional, Wahl, Daniel R, additional, Camelo-Piragua, Sandra, additional, Lieberman, Andrew P, additional, Venneti, Sriram, additional, McKeever, Paul, additional, Lawrence, Theodore, additional, Kurokawa, Ryo, additional, Sagher, Karen, additional, Altshuler, David, additional, Zhao, Lili, additional, Muraszko, Karin, additional, Castro, Maria G, additional, and Lowenstein, Pedro R, additional

Published
2023
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32. Transethnic genome-wide scan identifies novel Alzheimer's disease loci

Author

Adams, Perrie M., Albert, Marilyn S., Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Asthana, Sanjay, Atwood, Craig S., Barmada, Michjael M., Barnes, Lisa L., Beach, Thomas G., Becker, James T., Bigio, Eileen H., Bird, Thomas D., Blacker, Deborah, Boeve, Bradley F., Bowen, James D., Boxer, Adam, Burke, James R., Cairns, Nigel J., Cao, Chuanhai, Carlson, Chris S., Carlsson, Cynthia M., Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L., Chui, Helena C., Clark, David G., Corneveaux, Jason, Cribbs, David H., Crocco, Elizabeth A., Cruchaga, Carlos, De Jager, Philip L., DeCarli, Charles, DeKosky, Steven T., Demirci, F. Yesim, Dick, Malcolm, Dickson, Dennis W., Doody, Rachelle S., Duara, Ranjan, Ertekin-Taner, Nilufer, Faber, Kelley M., Fairchild, Thomas J., Fallon, Kenneth B., Farlow, Martin R., Ferris, Steven, Frosch, Matthew P., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Ghetti, Bernardino, Gilbert, John R., Glass, Jonathan D., Graff-Radford, Neill R., Green, Robert C., Growdon, John H., Hakonarson, Hakon, Hamilton, Ronald L., Hardy, John, Harrell, Lindy E., Head, Elizabeth, Honig, Lawrence S., Huebinger, Ryan M., Huentelman, Matthew J., Hulette, Christine M., Hyman, Bradley T., Jarvik, Gail P., Jicha, Gregory A., Jin, Lee-Way, Karydas, Anna, Kauwe, John S.K., Kaye, Jeffrey A., Kim, Ronald, Koo, Edward H., Kowall, Neil W., Kramer, Joel H., LaFerla, Frank M., Lah, James J., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Lin, Chiao-Feng, Lopez, Oscar L., Lyketsos, Constantine G., Mack, Wendy J., Marson, Daniel C., Martiniuk, Frank, Mash, Deborah C., Masliah, Eliezer, McCormick, Wayne C., McCurry, Susan M., McDavid, Andrew N., McKee, Ann C., Mesulam, Marsel, Miller, Bruce L., Miller, Carol A., Miller, Joshua W., Morris, John C., Mukherjee, Shubhabrata, Murrell, Jill R., Myers, Amanda J., O'Bryant, Sid, Olichney, John M., Pankratz, Vernon S., Parisi, Joseph E., Partch, Amanda, Paulson, Henry L., Perry, William, Peskind, Elaine, Petersen, Ronald C., Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reisch, Joan S., Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rogaeva, Ekaterina, Rosen, Howard J., Rosenberg, Roger N., Royall, Donald R., Sager, Mark A., Sano, Mary, Saykin, Andrew J., Schneider, Julie A., Schneider, Lon S., Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Tanzi, Rudolph E., Thornton-Wells, Tricia A., Trojanowski, John Q., Troncoso, Juan C., Tsuang, Debby W., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vardarajan, Badri N., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Williamson, Jennifer, Wishnek, Sarah, Woltjer, Randall L., Wright, Clinton B., Wu, Chuang-Kuo, Yu, Chang-En, Yu, Lei, Zhang, Xiaoling, Jun, Gyungah R., Chung, Jaeyoon, Mez, Jesse, Barber, Robert, Beecham, Gary W., Bennett, David A., Buxbaum, Joseph D., Byrd, Goldie S., Crane, Paul K., De Jager, Philip, Evans, Denis, Fallin, M. Danielle, Foroud, Tatiana M., Friedland, Robert P., Goate, Alison M., Hendrie, Hugh, Hall, Kathleen S., Hamilton-Nelson, Kara L., Inzelberg, Rivka, Kamboh, M. Ilyas, Kukull, Walter A., Kunkle, Brian W., Kuwano, Ryozo, Larson, Eric B., Logue, Mark W., Manly, Jennifer J., Martin, Eden R., Montine, Thomas J., Naj, Adam, Reiman, Eric M., Sherva, Richard, St. George-Hyslop, Peter H., Thornton, Timothy, Younkin, Steven G., Wang, Li-San, Wendlund, Jens R., Winslow, Ashley R., Haines, Jonathan, Mayeux, Richard, Pericak-Vance, Margaret A., Schellenberg, Gerard, Lunetta, Kathryn L., and Farrer, Lindsay A.

Published
2017
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33. Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction

Author

Nath, Samir R., Yu, Zhigang, Gipson, Theresa A., Marsh, Gregory B., Yoshidome, Eriko, Robins, Diane M., Todi, Sokol V., Housman, David E., and Lieberman, Andrew P.

Subjects
Androgen receptors -- Analysis, Skeletal muscle -- Research, RNA sequencing -- Research, Gene expression -- Research, Muscular diseases -- Development and progression -- Care and treatment, Transcription factors -- Analysis, Health care industry
Abstract

Skeletal muscle has emerged as a critical, disease-relevant target tissue in spinal and bulbar muscular atrophy, a degenerative disorder of the neuromuscular system caused by a CAG/polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. Here, we used RNA-sequencing (RNA-Seq) to identify pathways that are disrupted in diseased muscle using AR113Q knockin mice. This analysis unexpectedly identified substantially diminished expression of numerous ubiquitin/proteasome pathway genes in AR113Q muscle, encoding approximately 30% of proteasome subunits and 20% of E2 ubiquitin conjugases. These changes were age, hormone, and glutamine length dependent and arose due to a toxic gain of function conferred by the mutation. Moreover, altered gene expression was associated with decreased levels of the proteasome transcription factor NRF1 and its activator DDI2 and resulted in diminished proteasome activity. Ubiquitinated ADRM1 was detected in AR113Q muscle, indicating the occurrence of stalled proteasomes in mutant mice. Finally, diminished expression of Drosophila orthologues of NRF1 or ADRM1 promoted the accumulation of polyQ AR protein and increased toxicity. Collectively, these data indicate that AR113Q muscle develops progressive proteasome dysfunction that leads to the impairment of quality control and the accumulation of polyQ AR protein, key features that contribute to the age- dependent onset and progression of this disorder., Introduction Degeneration of the neuromuscular system is characteristic of the age-dependent phenotype that manifests in subjects with spinal and bulbar muscular atrophy (SBMA), a CAG/polyglutamine (polyQ) expansion disorder caused by [...]

Published
2018
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34. Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifiesLRRC4C, LHX5-AS1and nominates ancestry-specific lociPTPRK,GRB14, andKIAA0825as novel risk loci for Alzheimer’s disease: the Alzheimer’s Disease Genetics Consortium

Author

Rajabli, Farid, primary, Benchek, Penelope, additional, Tosto, Giuseppe, additional, Kushch, Nicholas, additional, Sha, Jin, additional, Bazemore, Katrina, additional, Zhu, Congcong, additional, Lee, Wan-Ping, additional, Haut, Jacob, additional, Hamilton-Nelson, Kara L., additional, Wheeler, Nicholas R., additional, Zhao, Yi, additional, Farrell, John J., additional, Grunin, Michelle A., additional, Leung, Yuk Yee, additional, Kuksa, Pavel P., additional, Li, Donghe, additional, Lucio da Fonseca, Eder, additional, Mez, Jesse B., additional, Palmer, Ellen L., additional, Pillai, Jagan, additional, Sherva, Richard M., additional, Song, Yeunjoo E., additional, Zhang, Xiaoling, additional, Iqbal, Taha, additional, Pathak, Omkar, additional, Valladares, Otto, additional, Kuzma, Amanda B., additional, Abner, Erin, additional, Adams, Perrie M., additional, Aguirre, Alyssa, additional, Albert, Marilyn S., additional, Albin, Roger L., additional, Allen, Mariet, additional, Alvarez, Lisa, additional, Apostolova, Liana G., additional, Arnold, Steven E., additional, Asthana, Sanjay, additional, Atwood, Craig S., additional, Ayres, Gayle, additional, Baldwin, Clinton T., additional, Barber, Robert C., additional, Barnes, Lisa L., additional, Barral, Sandra, additional, Beach, Thomas G., additional, Becker, James T., additional, Beecham, Gary W., additional, Beekly, Duane, additional, Benitez, Bruno A., additional, Bennett, David, additional, Bertelson, John, additional, Bird, Thomas D., additional, Blacker, Deborah, additional, Boeve, Bradley F., additional, Bowen, James D., additional, Boxer, Adam, additional, Brewer, James, additional, Burke, James R., additional, Burns, Jeffrey M., additional, Buxbaum, Joseph D., additional, Cairns, Nigel J., additional, Cantwell, Laura B., additional, Cao, Chuanhai, additional, Carlson, Christopher S., additional, Carlsson, Cynthia M., additional, Carney, Regina M., additional, Carrasquillo, Minerva M., additional, Chasse, Scott, additional, Chesselet, Marie-Francoise, additional, Chin, Nathaniel A., additional, Chui, Helena C., additional, Chung, Jaeyoon, additional, Craft, Suzanne, additional, Crane, Paul K., additional, Cribbs, David H., additional, Crocco, Elizabeth A., additional, Cruchaga, Carlos, additional, Cuccaro, Michael L., additional, Cullum, Munro, additional, Darby, Eveleen, additional, Davis, Barbara, additional, De Jager, Philip L., additional, DeCarli, Charles, additional, DeToledo, John, additional, Dick, Malcolm, additional, Dickson, Dennis W., additional, Dombroski, Beth A., additional, Doody, Rachelle S., additional, Duara, Ranjan, additional, Ertekin-Taner, NIlüfer, additional, Evans, Denis A., additional, Faber, Kelley M., additional, Fairchild, Thomas J., additional, Fallon, Kenneth B., additional, Fardo, David W., additional, Farlow, Martin R., additional, Fernandez-Hernandez, Victoria, additional, Ferris, Steven, additional, Foroud, Tatiana M., additional, Frosch, Matthew P., additional, Fulton-Howard, Brian, additional, Galasko, Douglas R., additional, Gamboa, Adriana, additional, Gearing, Marla, additional, Geschwind, Daniel H., additional, Ghetti, Bernardino, additional, Gilbert, John R., additional, Goate, Alison M., additional, Grabowski, Thomas J., additional, Graff-Radford, Neill R., additional, Green, Robert C., additional, Growdon, John H., additional, Hakonarson, Hakon, additional, Hall, James, additional, Hamilton, Ronald L., additional, Harari, Oscar, additional, Hardy, John, additional, Harrell, Lindy E., additional, Head, Elizabeth, additional, Henderson, Victor W., additional, Hernandez, Michelle, additional, Hohman, Timothy, additional, Honig, Lawrence S., additional, Huebinger, Ryan M., additional, Huentelman, Matthew J., additional, Hulette, Christine M., additional, Hyman, Bradley T., additional, Hynan, Linda S., additional, Ibanez, Laura, additional, Jarvik, Gail P., additional, Jayadev, Suman, additional, Jin, Lee-Way, additional, Johnson, Kim, additional, Johnson, Leigh, additional, Kamboh, M. Ilyas, additional, Karydas, Anna M., additional, Katz, Mindy J., additional, Kauwe, John S., additional, Kaye, Jeffrey A., additional, Keene, C. Dirk, additional, Khaleeq, Aisha, additional, Kim, Ronald, additional, Knebl, Janice, additional, Kowall, Neil W., additional, Kramer, Joel H., additional, Kukull, Walter A., additional, LaFerla, Frank M., additional, Lah, James J., additional, Larson, Eric B., additional, Lerner, Alan, additional, Leverenz, James B., additional, Levey, Allan I., additional, Lieberman, Andrew P., additional, Lipton, Richard B., additional, Logue, Mark, additional, Lopez, Oscar L., additional, Lunetta, Kathryn L., additional, Lyketsos, Constantine G., additional, Mains, Douglas, additional, Margaret, Flanagan E., additional, Marson, Daniel C., additional, Martin, Eden R R., additional, Martiniuk, Frank, additional, Mash, Deborah C., additional, Masliah, Eliezer, additional, Massman, Paul, additional, Masurkar, Arjun, additional, McCormick, Wayne C., additional, McCurry, Susan M., additional, McDavid, Andrew N., additional, McDonough, Stefan, additional, McKee, Ann C., additional, Mesulam, Marsel, additional, Miller, Bruce L., additional, Miller, Carol A., additional, Miller, Joshua W., additional, Montine, Thomas J., additional, Monuki, Edwin S., additional, Morris, John C., additional, Mukherjee, Shubhabrata, additional, Myers, Amanda J., additional, Nguyen, Trung, additional, O’Bryant, Sid, additional, Olichney, John M., additional, Ory, Marcia, additional, Palmer, Raymond, additional, Parisi, Joseph E., additional, Paulson, Henry L., additional, Pavlik, Valory, additional, Paydarfar, David, additional, Perez, Victoria, additional, Peskind, Elaine, additional, Petersen, Ronald C., additional, Pierce, Aimee, additional, Polk, Marsha, additional, Poon, Wayne W., additional, Potter, Huntington, additional, Qu, Liming, additional, Quiceno, Mary, additional, Quinn, Joseph F., additional, Raj, Ashok, additional, Raskind, Murray, additional, Reiman, Eric M., additional, Reisberg, Barry, additional, Reisch, Joan S., additional, Ringman, John M., additional, Roberson, Erik D., additional, Rodriguear, Monica, additional, Rogaeva, Ekaterina, additional, Rosen, Howard J., additional, Rosenberg, Roger N., additional, Royall, Donald R., additional, Sager, Mark A., additional, Sano, Mary, additional, Saykin, Andrew J., additional, Schneider, Julie A., additional, Schneider, Lon S., additional, Seeley, William W., additional, Slifer, Susan H., additional, Small, Scott, additional, Smith, Amanda G., additional, Smith, Janet P., additional, Sonnen, Joshua A., additional, Spina, Salvatore, additional, St George-Hyslop, Peter, additional, Stern, Robert A., additional, Stevens, Alan B., additional, Strittmatter, Stephen M., additional, Sultzer, David, additional, Swerdlow, Russell H., additional, Tanzi, Rudolph E., additional, Tilson, Jeffrey L., additional, Trojanowski, John Q., additional, Troncoso, Juan C., additional, Tsuang, Debby W., additional, Van Deerlin, Vivianna M., additional, van Eldik, Linda J., additional, Vance, Jeffery M., additional, Vardarajan, Badri N., additional, Vassar, Robert, additional, Vinters, Harry V., additional, Vonsattel, Jean-Paul, additional, Weintraub, Sandra, additional, Welsh-Bohmer, Kathleen A., additional, Whitehead, Patrice L., additional, Wijsman, Ellen M., additional, Wilhelmsen, Kirk C., additional, Williams, Benjamin, additional, Williamson, Jennifer, additional, Wilms, Henrik, additional, Wingo, Thomas S., additional, Wisniewski, Thomas, additional, Woltjer, Randall L., additional, Woon, Martin, additional, Wright, Clinton B., additional, Wu, Chuang-Kuo, additional, Younkin, Steven G., additional, Yu, Chang-En, additional, Yu, Lei, additional, Zhu, Xiongwei, additional, Kunkle, Brian W., additional, Bush, William S., additional, Wang, Li-San, additional, Farrer, Lindsay A., additional, Haines, Jonathan L., additional, Mayeux, Richard, additional, Pericak-Vance, Margaret A., additional, Schellenberg, Gerard D., additional, Jun, Gyungah R., additional, Reitz, Christiane, additional, and Naj, Adam C., additional

Published
2023
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38. Data from Rapid Intraoperative Diagnosis of Pediatric Brain Tumors Using Stimulated Raman Histology

Author

Hollon, Todd C., primary, Lewis, Spencer, primary, Pandian, Balaji, primary, Niknafs, Yashar S., primary, Garrard, Mia R., primary, Garton, Hugh, primary, Maher, Cormac O., primary, McFadden, Kathryn, primary, Snuderl, Matija, primary, Lieberman, Andrew P., primary, Muraszko, Karin, primary, Camelo-Piragua, Sandra, primary, and Orringer, Daniel A., primary

Published
2023
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39. Table S2 from Rapid Intraoperative Diagnosis of Pediatric Brain Tumors Using Stimulated Raman Histology

Author

Hollon, Todd C., primary, Lewis, Spencer, primary, Pandian, Balaji, primary, Niknafs, Yashar S., primary, Garrard, Mia R., primary, Garton, Hugh, primary, Maher, Cormac O., primary, McFadden, Kathryn, primary, Snuderl, Matija, primary, Lieberman, Andrew P., primary, Muraszko, Karin, primary, Camelo-Piragua, Sandra, primary, and Orringer, Daniel A., primary

Published
2023
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40. Supplementary Figure 1 from Rapid Intraoperative Diagnosis of Pediatric Brain Tumors Using Stimulated Raman Histology

Author

Hollon, Todd C., primary, Lewis, Spencer, primary, Pandian, Balaji, primary, Niknafs, Yashar S., primary, Garrard, Mia R., primary, Garton, Hugh, primary, Maher, Cormac O., primary, McFadden, Kathryn, primary, Snuderl, Matija, primary, Lieberman, Andrew P., primary, Muraszko, Karin, primary, Camelo-Piragua, Sandra, primary, and Orringer, Daniel A., primary

Published
2023
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41. Supplementary Figure 2 from Rapid Intraoperative Diagnosis of Pediatric Brain Tumors Using Stimulated Raman Histology

Author

Hollon, Todd C., primary, Lewis, Spencer, primary, Pandian, Balaji, primary, Niknafs, Yashar S., primary, Garrard, Mia R., primary, Garton, Hugh, primary, Maher, Cormac O., primary, McFadden, Kathryn, primary, Snuderl, Matija, primary, Lieberman, Andrew P., primary, Muraszko, Karin, primary, Camelo-Piragua, Sandra, primary, and Orringer, Daniel A., primary

Published
2023
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42. Deubiquitinase USP7 contributes to the pathogenicity of spinal and bulbar muscular atrophy

Author

Pluciennik, Anna, Liu, Yuhong, Molotsky, Elana, Marsh, Gregory B., Ranxhi, Bedri, Arnold, Frederick J., St.-Cyr, Sophie, Davidson, Beverly, Pourshafie, Naemeh, Lieberman, Andrew P., Gu, Wei, Todi, Sokol V., and Merry, Diane E.

Subjects
Ubiquitin-proteasome system -- Health aspects, Glutamine -- Physiological aspects -- Health aspects, Spinal muscular atrophy -- Development and progression -- Genetic aspects, Health care industry
Abstract

Polyglutamine (polyQ) diseases are devastating, slowly progressing neurodegenerative conditions caused by expansion of polyQ-encoding CAG repeats within the coding regions of distinct, unrelated genes. In spinal and bulbar muscular atrophy (SBMA), polyQ expansion within the androgen receptor (AR) causes progressive neuromuscular toxicity, the molecular basis of which is unclear. Using quantitative proteomics, we identified changes in the AR interactome caused by polyQ expansion. We found that the deubiquitinase USP7 preferentially interacts with polyQ- expanded AR and that lowering USP7 levels reduced mutant AR aggregation and cytotoxicity in cell models of SBMA. Moreover, USP7 knockdown suppressed disease phenotypes in SBMA and spinocerebellar ataxia type 3 (SCA3) fly models, and monoallelic knockout of Usp7 ameliorated several motor deficiencies in transgenic SBMA mice. USP7 overexpression resulted in reduced AR ubiquitination, indicating the direct action of USP7 on AR. Using quantitative proteomics, we identified the ubiquitinated lysine residues on mutant AR that are regulated by USP7. Finally, we found that USP7 also differentially interacts with mutant Huntingtin (HTT) protein in striatum and frontal cortex of a knockin mouse model of Huntington's disease. Taken together, our findings reveal a critical role for USP7 in the pathophysiology of SBMA and suggest a similar role in SCA3 and Huntington's disease., Introduction Spinal and bulbar muscular atrophy (SBMA) is 1 of 9 polyQ diseases that are part of a larger family of neurodegenerative diseases characterized by protein misfolding and accumulation; these [...]

Published
2021
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44. Species-specific differences in NPC1 protein trafficking govern therapeutic response in Niemann-Pick type C disease

Author

Schultz, Mark L., primary, Schache, Kylie J., additional, Azaria, Ruth D., additional, Kuiper, Esmée Q., additional, Erwood, Steven, additional, Ivakine, Evgueni A., additional, Farhat, Nicole Y., additional, Porter, Forbes D., additional, Pathmasiri, Koralege C., additional, Cologna, Stephanie M., additional, Uhler, Michael D., additional, and Lieberman, Andrew P., additional

Published
2022
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45. A non-randomized, open-label, dose-finding, first-in-human trial of combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: transgene expression persists up to 17 months post-vector injection

Author

Umemura, Yoshie, primary, Orringer, Daniel, additional, Junck, Larry, additional, Varela, Maria L., additional, West, Molly E.J., additional, Faisal, Syed M., additional, Comba, Andrea, additional, Heth, Jason, additional, Sagher, Oren, additional, Leung, Denise, additional, Mammoser, Aaron, additional, Hervey-Jumper, Shawn, additional, Zamler, Daniel, additional, Yadav, Viveka N., additional, Dunn, Patrick, additional, Al-Holou, Wajd, additional, Hollon, Todd, additional, Kim, Michelle M., additional, Wahl, Daniel R., additional, Camelo-Piragua, Sandra, additional, Lieberman, Andrew P., additional, Venneti, Sriram, additional, McKeever, Paul, additional, Lawrence, Theodore, additional, Kurokawa, Ryo, additional, Sagher, Karen, additional, Altshuler, David, additional, Zhao, Lili, additional, Muraszko, Karin, additional, Castro, Maria G., additional, and Lowenstein, Pedro R., additional

Published
2022
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48. Blood-brain barrier–adapted precision medicine therapy for pediatric brain tumors

Author

Marini, Bernard L., Benitez, Lydia L., Zureick, Andrew H., Salloum, Ralph, Gauthier, Angela C., Brown, Julia, Wu, Yi-Mi, Robinson, Dan R., Kumar, Chandan, Lonigro, Robert, Vats, Pankaj, Cao, Xuhong, Kasaian, Katayoon, Anderson, Bailey, Mullan, Brendan, Chandler, Benjamin, Linzey, Joseph R., Camelo-Piragua, Sandra I., Venneti, Sriram, McKeever, Paul E., McFadden, Kathryn A., Lieberman, Andrew P., Brown, Noah, Shao, Lina, Leonard, Marcia A.S., Junck, Larry, McKean, Erin, Maher, Cormac O., Garton, Hugh J.L., Muraszko, Karin M., Hervey-Jumper, Shawn, Mulcahy-Levy, Jean M., Green, Adam, Hoffman, Lindsey M., Dorris, Katie, Vitanza, Nicholas A., Wang, Joanne, Schwartz, Jonathan, Lulla, Rishi, Smiley, Natasha Pillay, Bornhorst, Miriam, Haas-Kogan, Daphne A., Robertson, Patricia L., Chinnaiyan, Arul M., Mody, Rajen, and Koschmann, Carl

Published
2017
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50. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author

Chauhan, Ganesh, Adams, Hieab H.H., Satizabal, Claudia L., Bis, Joshua C., Teumer, Alexander, Sargurupremraj, Muralidharan, Hofer, Edith, Trompet, Stella, Hilal, Saima, Smith, Albert Vernon, Jian, Xueqiu, Malik, Rainer, Traylor, Matthew, Pulit, Sara L., Amouyel, Philippe, Mazoyer, Bernard, Zhu, Yi-Cheng, Kaffashian, Sara, Schilling, Sabrina, Beecham, Gary W., Montine, Thomas J., Schellenberg, Gerard D., Kjartansson, Olafur, Guðnason, Vilmundur, Knopman, David S., Griswold, Michael E., Windham, B. Gwen, Gottesman, Rebecca F., Mosley, Thomas H., Schmidt, Reinhold, Saba, Yasaman, Schmidt, Helena, Takeuchi, Fumihiko, Yamaguchi, Shuhei, Nabika, Toru, Kato, Norihiro, Rajan, Kumar B., Aggarwal, Neelum T., De Jager, Philip L., Evans, Denis A., Psaty, Bruce M., Rotter, Jerome I., Rice, Kenneth, Lopez, Oscar L., Liao, Jiemin, Chen, Christopher, Cheng, Ching-Yu, Wong, Tien Y., Ikram, Mohammad K., van der Lee, Sven J., Amin, Najaf, Chouraki, Vincent, DeStefano, Anita L., Aparicio, Hugo J., Romero, Jose R., Maillard, Pauline, DeCarli, Charles, Wardlaw, Joanna M., Hernández, Maria del C. Valdés, Luciano, Michelle, Liewald, David, Deary, Ian J., Starr, John M., Bastin, Mark E., Muñoz Maniega, Susana, Slagboom, P. Eline, Beekman, Marian, Deelen, Joris, Uh, Hae-Won, Lemmens, Robin, Brodaty, Henry, Wright, Margaret J., Ames, David, Boncoraglio, Giorgio B., Hopewell, Jemma C., Beecham, Ashley H., Blanton, Susan H., Wright, Clinton B., Sacco, Ralph L., Wen, Wei, Thalamuthu, Anbupalam, Armstrong, Nicola J., Chong, Elizabeth, Schofield, Peter R., Kwok, John B., van der Grond, Jeroen, Stott, David J., Ford, Ian, Jukema, J. Wouter, Vernooij, Meike W., Hofman, Albert, Uitterlinden, André G., van der Lugt, Aad, Wittfeld, Katharina, Grabe, Hans J., Hosten, Norbert, von Sarnowski, Bettina, Völker, Uwe, Levi, Christopher, Jimenez-Conde, Jordi, Sharma, Pankaj, Sudlow, Cathie L.M., Rosand, Jonathan, Woo, Daniel, Cole, John W., Meschia, James F., Slowik, Agnieszka, Thijs, Vincent, Lindgren, Arne, Melander, Olle, Grewal, Raji P., Rundek, Tatjana, Rexrode, Kathy, Rothwell, Peter M., Arnett, Donna K., Jern, Christina, Johnson, Julie A., Benavente, Oscar R., Wasssertheil-Smoller, Sylvia, Lee, Jin-Moo, Wong, Quenna, Mitchell, Braxton D., Rich, Stephen S., McArdle, Patrick F., Geerlings, Mirjam I., van der Graaf, Yolanda, de Bakker, Paul I.W., Asselbergs, Folkert W., Srikanth, Velandai, Thomson, Russell, McWhirter, Rebekah, Moran, Chris, Callisaya, Michele, Phan, Thanh, Rutten-Jacobs, Loes C.A., Bevan, Steve, Tzourio, Christophe, Mather, Karen A., Sachdev, Perminder S., van Duijn, Cornelia M., Worrall, Bradford B., Dichgans, Martin, Kittner, Steven J., Markus, Hugh S., Ikram, Mohammad A., Fornage, Myriam, Launer, Lenore J., Seshadri, Sudha, Longstreth, W.T., Jr, Debette, Stéphanie, Almgren, Peter, Anderson, Christopher D., Arnett, Donna K., Attia, John, Ay, Hakan, Benavente, Oscar R., Bevan, Steve, Brown, Robert D., Bustamante, Mariana, Cheng, Yu-Ching, Cole, John W., Cotlarciuc, Ioana, Cruchaga, Carlos, de Bakker, Paul IW., Delavaran, Hossein, Dichgans, Martin, Engström, Gunnar, Fornage, Myriam, Grewal, Raji P., Heitsch, Laura, Holliday, Elizabeth, Ibanez, Laure, Ilinca, Andreea, Irvin, Marguerite R., Jackson, Rebecca D., Jern, Christina, Jimenez-Conde, Jordi, Johnson, Julie A., Jood, Katarina, Kissela, Brett M., Kittner, Steven J., Kleindorfer, Dawn O., Labovitz, Daniel, Laurie, Cathy C., Lee, Jin-Moo, Lemmens, Robin, Levi, Christopher, Li, Linxin, Lindgren, Arne G., Maguire, Jane, Markus, Hugh S., McArdle, Patrick F., Melander, Olle, Meschia, James F., Mitchell, Braxton D., Müller-Nurasyid, Martina, Norrving, Bo, Peddareddygari, Leema Reddy, Pera, Joanna, Pulit, Sara L., Rexrode, Kathryn, Ribasés, Marta, Roquer, Jaume, Rost, Natalia S., Rothwell, Peter M., Rundek, Tatjana, Sacco, Ralph L., Schmidt, Reinhold, Sharma, Pankaj, Slowik, Agnieszka, Soriano-Tárraga, Carolina, Stanne, Tara, Stauch, Konstantin, Stine, O C., Sudlow, Cathie LM., Thijs, Vincent N.S., Wasssertheil-Smoller, Sylvia, Weir, David, Williams, Stephen R., Wong, Quenna, Woo, Daniel, Worrall, Bradford B., Xu, Huichun, Seshadri, Sudha, Hyacinth, Hyacinth I, Marini, Sandro, Nyquist, Paul, Lewis, Cathryn, Hansen, Bjorn, Norrving, Bo, Rosand, Jonathan, Biffi, Alessandro, Kourkoulis, Christina, Anderson, Chris, Giese, Anne-Katrin, Sacco, Ralph, Sharma, Pankaj, Chung, Jong-Won, Kim, Gyeong-Moon, Lubitz, Steven, Bourcier, Romain, Howson, Joanna, Granata, Alessandra, Drazyk, Anna, Markus, Hugh, Wardlaw, Joanna, Mitchell, Braxton, Cole, John, Hopewell, Jemma, Walters, Robin, Turnbull, Iain, Worrall, Bradford, Bis, Josh, Reiner, Alex, Dhar, Raj, Heitsch, Laura, Lee, Jin-Moo, Prasad, Kameshwar, Sarnowski, Chloé, Aparicio, Hugo Javier, Yang, Qiong, Chasman, Daniel, Rexrode, Kathryn, Phuah, Chia-Ling, Liu, Guiyou, Elkind, Mitchell, Lange, Leslie, Rost, Natalia, James, Michael, Stewart, Jill, Vojinovic, Dina, Thijs, Vincent, Parati, Eugenio, Boncoraglio, Giorgio, Zand, Ramin, Bijlenga, Philippe, Selim, Magdy, Grond-Ginsbach, Caspar, Strbian, Daniel, Tomppo, Liisa, Sallinen, Hanne, Pfeiffer, Dorothea, Torres, Nuria, Barboza, Miguel, Laarman, Melanie, Carriero, Roberta, Holliday, Elizabeth, Jimenez-Conde, Jordi, Soriano, Carolina, Gill, Dipender, Debette, Stephanie, Mishra, Aniket, Wu, Jer-Yuarn, Ko, Tai-Ming, Bione, Silvia, Jood, Katarina, Tatlisumak, Turgut, Holmegaard, Lukas, Yue, Suo, bersano, Anna, Pera, Joanna, Slowik, Agnieszka, Levi, Christopher, Schlicht, Kristina, Lemmens, Robin, Ninomiya, Toshiharu, Oberstein, Saskia Lesnik, Lee, Tsong-Hai, Malik, Rainer, Dichgans, Martin, Lindgren, Arne, Wasselius, Johan, Drake, Mattias, Melander, Olle, Stenman, Martin, Ilinca, Andreea, Crawford, Katherine, Lena, Umme, Mateen, Farrah, Ay, Hakan, Wu, Ona, Schirmer, Markus, Cramer, Steve, Golland, Polina, Brown, Robert, Meschia, James, Ross, Owen A., Pare, Guillaume, Chong, Mike, Rundek, Tatjana, Gwinn, Katrina, Chen, Christopher, Koenig, Jim, Giralt, Eva, Saleheen, Danish, de Leeuw, Frank-Erik, Klijn, Karin, Kamatani, Yoichiro, Kubo, Michiaki, Okada, Yukinori, Pedersen, Annie, Olsson, Maja, Martín, Juan José, Xu, Huichun, Tan, Eng King, Frid, Petrea, Lee, Chaeyoung, Tregouet, David, Leung, Thomas, Choy, Richard, Jern, Christina, Loo, Keat Wei, Rinkel, Gabriel, Franca, Paulo, Cendes, Iscia, Carrera, Caty, Fernandez-Cadenas, Israel, Montaner, Joan, Kim, Helen, Owolabi, Mayowa, Sofat, Reecha, Bakker, Mark, Ruigrok, Ynte, Hauer, Allard, Pulit, Sara L., van der Laan, Sander W., Irvin, Ryan, Sargurupremraj, Murali, Pezzini, Alessandro, Abd-Allah, Foad, Liebeskind, David, Traylor, Matthew, Tan, Rhea, Danesh, John, Rutten-Jacobs, Loes, Donatti, Amanda, Avelar, Wagner, Broderick, Joseph, Woo, Daniel, Sudlow, Cathie, Rannikmae, Kristiina, McDonough, Caitrin Wheeler, van Agtmael, Tom, Walters, Matthew, Söderholm, Martin, Lorentzen, Erik, Olsson, Sandra, Stanne, Tara, Olsson, Martina, Akinyemi, Rufus, Cotlatciuc, Ioana, McArdle, Patrick, Dave, Tushar, Kittner, Steven, Attia, John, Faber, James E, Millwood, Iona, Márquez, Elsa Valdés, Mancuso, Michelangelo, Vibo, Riina, Korv, Janika, Maguire, Jane, Fornage, Myriam, Majersik, Jennifer, DeHavenon, Adam, Alexander, Matthew, Sale, Michele, Southerland, Andrew, Owens, Debra, Psaty, Bruce, Longstreth, W. T., Jr, Wolfe, Stacey Quintero, Langefeld, Carl, Cruchaga, Carlos, Konrad, Jan, Sheth, Kevin, Falcone, Guido, Donahue, Kathleen, Simpkins, Alexis N, Liang Byorn, Tan Wei, Chan, Bernard, Clatworthy, Phil, Florez, Jose, Harshfield, Eric, Hozawa, Atsushi, Hsu, Chung, Hu, Chaur-Jong, Ibanez, Laure, Ihara, Masafumi, Lange, Marcos, Lee, Soo Ji, Lee, I-Hui, Musolino, Patricia, Nakatomi, Hirofumi, Park, Kwang-Yeol, Rich, Stephen S, Riley, Chris, Sung, Joohon, Suzuki, Hideaki, Vo, Katie, Washida, Kazuo, Ibenez, Laura Garcia, Slowik, Agnieszka, Hofman, Albert, Algra, Ale, Reiner, Alex P, Doney, Alexander S F, Gschwendtner, Andreas, Ilinca, Andreea, Giese, Anne-Katrin, Lindgren, Arne, Vicente, Astrid M, Norrving, Bo, Nordestgaard, Børge G, Mitchell, Braxton D, Worrall, Bradford B, Psaty, Bruce M, Carty, Cara L, Sudlow, Cathie, Anderson, Christopher D, Levi, Christopher, Satizabal, Claudia L, Palmer, Colin N A, Gamble, Dale M, Woo, Daniel, Saleheen, Danish, Ringelstein, E Bernd, Valdimarsson, Einar, Holliday, Elizabeth, Davies, Gail, Chauhan, Ganesh, Pasterkamp, Gerard, Boncoraglio, Giorgio, Kuhlenbäumer, Gregor, Thorleifsson, Gudmar, Falcone, Guido J, Pare, Guillame, Schmidt, Helena, Delavaran, Hossein, Markus, Hugh S, Aparicio, Hugo J, Deary, Ian, Cotlarciuc, Ioana, Fernandez-Cadenas, Israel, Meschia, James, Hopewell, Jemma C, Liu, Jingmin, Montaner, Joan, Pera, Joanna, Cole, John, Attia, John R, Rosand, Jonathan, Ferro, Jose M, Bis, Joshua, Furie, Karen, Stefansson, Kari, Berger, Klaus, Kostulas, Konstantinos, Rannikmae, Kristina, Ikram, M Arfan, Benn, Marianne, Dichgans, Martin, Farrall, Martin, Pandolfo, Massimo, Traylor, Matthew, Walters, Matthew, Sale, Michele, Nalls, Mike, Fornage, Myriam, van Zuydam, Natalie R, Sharma, Pankaj, Abrantes, Patricia, de Bakker, Paul IW, Higgins, Peter, Lichtner, Peter, Rothwell, Peter M, Amouyel, Philippe, Yang, Qiong, Malik, Rainer, Schmidt, Reinhold, Clarke, Robert, Lemmens, Robin, van der Laan, Sander W, Pulit, Sara L, Abboud, Sherine, Oliveira, Sofia A, Gretarsdottir, Solveig, Debette, Stephanie, Williams, Stephen R, Bevan, Steve, Kittner, Steven J, Seshadri, Sudha, Mosley, Thomas, Battey, Thomas WK, Tatlisumak, Turgut, Thorsteinsdottir, Unnur, Thijs, Vincent NS, Longstreth, W T, Zhao, Wei, Chen, Wei-Min, Cheng, Yu-Ching, Albert, Marilyn S., Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Asthana, Sanjay, Atwood, Craig S., Baldwin, Clinton T., Barmada, M. Michael, Barnes, Lisa L., Barral, Sandra, Beach, Thomas G., Becker, James T., Beecham, Gary W., Beekly, Duane, Bennett, David A., Bigio, Eileen H., Bird, Thomas D., Blacker, Deborah, Boeve, Bradley F., Boxer, Adam, Burke, James R., Burns, Jeffrey M., Buxbaum, Joseph D., Byrd, Goldie S., Cai, Guiqing, Cairns, Nigel J., Cantwell, Laura B., Cao, Chuanhai, Carlsson, Cynthia M., Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L., Chui, Helena C., Clark, David G., Cribbs, David H., Crocco, Elizabeth A., Cruchaga, Carlos, De Jager, Philip L., DeCarli, Charles, Demirci, F. Yesim, Dick, Malcolm, Dickson, Dennis W., Duara, Ranjan, Ertekin-Taner, Nilufer, Evans, Denis A., Faber, Kelley M., Fallin, M. Daniele, Fallon, Kenneth B., Fardo, David W., Farlow, Martin R., Farrer, Lindsay A., Ferris, Steven, Foroud, Tatiana M., Frosch, Matthew P., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Ghetti, Bernardino, Gilbert, John R., Go, Rodney C.P., Goate, Alison M., Graff-Radford, Neill R., Green, Robert C., Griffith, Patrick, Growdon, John H., Haines, Jonathan L., Hakonarson, Hakon, Hamilton, Ronald L., Hamilton-Nelson, Kara L., Haroutunian, Vahram, Harrell, Lindy E., Honig, Lawrence S., Huebinger, Ryan M., Hulette, Christine M., Hyman, Bradley T., Jicha, Gregory A., Jin, Lee-Way, Jun, Gyungah, Kamboh, M. Ilyas, Karydas, Anna, Kauwe, John S.K., Kaye, Jeffrey A., Kim, Ronald, Kowall, Neil W., Kramer, Joel H., Kukull, Walter A., Kunkle, Brian W., LaFerla, Frank M., Lah, James J., Lang-Walker, Rosalyn, Larson, Eric B., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Logue, Mark W., Lopez, Oscar L., Lunetta, Kathryn L., Lyketsos, Constantine G., Mack, Wendy J., Manly, Jennifer J., Marson, Daniel C., Martin, Eden R., Martiniuk, Frank, Mash, Deborah C., Masliah, Eliezer, Mayeux, Richard, McKee, Ann C., Mesulam, Marsel, Miller, Bruce L., Miller, Carol A., Miller, Joshua W., Montine, Thomas J., Morris, John C., Murrell, Jill R., Naj, Adam C., Obisesan, Thomas O., Olichney, John M., Pankratz, Vernon S., Parisi, Joseph E., Partch, Amanda, Paulson, Henry L., Pericak-Vance, Margaret A., Perry, William, Peskind, Elaine, Petersen, Ronald C., Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raj, Towfique, Raskind, Murray, Reiman, Eric M., Reisberg, Barry, Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rosen, Howard J., Rosenberg, Roger N., Sager, Mark A., Sano, Mary, Saykin, Andrew J., Schellenberg, Gerard D., Schneider, Julie A., Schneider, Lon S., Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tanzi, Rudolph E., Thornton-Wells, Tricia A., Trojanowski, John Q., Troncoso, Juan C., Tsuang, Debby W., Valladares, Otto, Van Deerlin, Vivianna M., Van Eldik, Linda J., Vardarajan, Badri N., Vinters, Harry V., Vonsattel, Jean Paul, Wang, Li-San, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Williamson, Jennifer, Wingo, Thomas S., Wishnek, Sarah, Woltjer, Randall L., Wright, Clinton B., Younkin, Steven G., Yu, Chang-En, Yu, Lei, Chauhan, Ganesh, Chu, Audrey Y., Fornage, Myriam, Bis, Joshua C., Havulinna, Aki S., Sargurupremraj, Muralidharan, Smith, Albert Vernon, Adams, Hieab H.H., Choi, Seung Hoan, Trompet, Stella, Garcia, Melissa E., Manichaikul, Ani, Teumer, Alexander, Gustafsson, Stefan, Bartz, Traci M., Bellenguez, Céline, Vidal, Jean Sebastien, Jian, Xueqiu, Kjartansson, Olafur, Wiggins, Kerri L., Satizabal, Claudia L., Xue, Flora, Ripatti, Samuli, Liu, Yongmei, Deelen, Joris, Hoed, Marcel den, Heckbert, Susan R., Rice, Kenneth, Smith, Nicholas L., Wong, Quenna, Aparicio, Hugo J., Buring, Julie E., Ridker, Paul M, Berr, Claudine, Dartigues, Jean-François, Hamsten, Anders, Magnusson, Patrik K., Pedersen, Nancy L., Lannfelt, Lars, Lind, Lars, Lindgren, Cecilia M., Morris, Andrew P., Hofman, Albert, Koudstaal, Peter J., Portegies, Marileen LP., Uitterlinden, André G., de Craen, Anton JM, Ford, Ian, Jukema, J. Wouter, Stott, David J, Allen, Norrina B., Sale, Michele M., Johnson, Andrew D, Bennett, David A., De Jager, Philip L., White, Charles C., Grabe, Hans Jörgen, Paulista Markus, Marcello Ricardo, Lopez, Oscar L, Rotter, Jerome I., Nalls, Michael A., Gottesman, Rebecca F., Griswold, Michael E., Knopman, David S., Windham, B. Gwen, Beiser, Alexa, Vartiainen, Erkki, French, Curtis R., Kurth, Tobias, Psaty, Bruce M., Harris, Tamara B., Rich, Stephen S, deStefano, Anita L., Schmidt, Carsten Oliver, Salomaa, Veikko, Mosley, Thomas H., Ingelsson, Erik, van Duijn, Cornelia M., Tzourio, Christophe, Launer, Lenore J, Ikram, M. Arfan, Chasman, Daniel I., Longstreth, W. T., Jr, Seshadri, Sudha, Debette, Stéphanie, Verhaaren, Benjamin F.J., Debette, Stéphanie, Bis, Joshua C., Smith, Jennifer A., Ikram, M. Kamran, Adams, Hieab H., Beecham, Ashley H., Rajan, Kumar B., Lopez, Lorna M., Barral, Sandra, van Buchem, Mark A., van der Grond, Jeroen, Smith, Albert V., Hegenscheid, Katrin, Aggarwal, Neelum T., de Andrade, Mariza, Atkinson, Elizabeth J., Beekman, Marian, Beiser, Alexa S., Blanton, Susan H., Boerwinkle, Eric, Brickman, Adam M., Bryan, R. Nick, Chauhan, Ganesh, Chen, Christopher P.L.H., Chouraki, Vincent, de Craen, Anton J.M., Crivello, Fabrice, Deary, Ian J., Deelen, Joris, De Jager, Philip L., Dufouil, Carole, Elkind, Mitchell S.V., Evans, Denis A., Freudenberger, Paul, Gottesman, Rebecca F., Guðnason, Vilmundur, Habes, Mohamad, Heckbert, Susan R., Heiss, Gerardo, Hilal, Saima, Hofer, Edith, Hofman, Albert, Ibrahim-Verbaas, Carla A., Knopman, David S., Lewis, Cora E., Liao, Jiemin, Liewald, David C.M., Luciano, Michelle, van der Lugt, Aad, Martinez, Oliver O., Mayeux, Richard, Mazoyer, Bernard, Nalls, Mike, Nauck, Matthias, Niessen, Wiro J., Oostra, Ben A., Psaty, Bruce M., Rice, Kenneth M., Rotter, Jerome I., von Sarnowski, Bettina, Schmidt, Helena, Schreiner, Pamela J., Schuur, Maaike, Sidney, Stephen S., Sigurdsson, Sigurdur, Slagboom, P. Eline, Stott, David J.M., van Swieten, John C., Teumer, Alexander, Töglhofer, Anna Maria, Traylor, Matthew, Trompet, Stella, Turner, Stephen T., Tzourio, Christophe, Uh, Hae-Won, Uitterlinden, André G., Vernooij, Meike W., Wang, Jing J., Wong, Tien Y., Wardlaw, Joanna M., Windham, B. Gwen, Wittfeld, Katharina, Wolf, Christiane, Wright, Clinton B., Yang, Qiong, Zhao, Wei, Zijdenbos, Alex, Jukema, J. Wouter, Sacco, Ralph L., Kardia, Sharon L.R., Amouyel, Philippe, Mosley, Thomas H., Longstreth, W. T., Jr, DeCarli, Charles C., van Duijn, Cornelia M., Schmidt, Reinhold, Launer, Lenore J., Grabe, Hans J., Seshadri, Sudha S., Ikram, M. Arfan, Fornage, Myriam, Bis, Joshua C., Kavousi, Maryam, Franceschini, Nora, Isaacs, Aaron, Abecasis, Gonçalo R, Schminke, Ulf, Post, Wendy, Smith, Albert V., Cupples, L. Adrienne, Markus, Hugh S, Schmidt, Reinhold, Huffman, Jennifer E., Lehtimäki, Terho, Baumert, Jens, Münzel, Thomas, Heckbert, Susan R., Dehghan, Abbas, North, Kari, Oostra, Ben, Bevan, Steve, Stoegerer, Eva-Maria, Hayward, Caroline, Raitakari, Olli, Meisinger, Christa, Schillert, Arne, Sanna, Serena, Völzke, Henry, Cheng, Yu-Ching, Thorsson, Bolli, Fox, Caroline S., Rice, Kenneth, Rivadeneira, Fernando, Nambi, Vijay, Halperin, Eran, Petrovic, Katja E., Peltonen, Leena, Wichmann, H. Erich, Schnabel, Renate B., Dörr, Marcus, Parsa, Afshin, Aspelund, Thor, Demissie, Serkalem, Kathiresan, Sekar, Reilly, Muredach P., Taylor, Kent, Uitterlinden, Andre, Couper, David J., Sitzer, Matthias, Kähönen, Mika, Illig, Thomas, Wild, Philipp S., Orru, Marco, Lüdemann, Jan, Shuldiner, Alan R., Eiriksdottir, Gudny, White, Charles C., Rotter, Jerome I., Hofman, Albert, Seissler, Jochen, Zeller, Tanja, Usala, Gianluca, Ernst, Florian, Launer, Lenore J., DʼAgostino, Ralph B., Sr, OʼLeary, Daniel H., Ballantyne, Christie, Thiery, Joachim, Ziegler, Andreas, Lakatta, Edward G., Chilukoti, Ravi Kumar, Harris, Tamara B., Wolf, Philip A., Psaty, Bruce M., Polak, Joseph F, Li, Xia, Rathmann, Wolfgang, Uda, Manuela, Boerwinkle, Eric, Klopp, Norman, Schmidt, Helena, Wilson, James F, Viikari, Jorma, Koenig, Wolfgang, Blankenberg, Stefan, Newman, Anne B., Witteman, Jacqueline, Heiss, Gerardo, van Duijn, Cornelia, Scuteri, Angelo, Homuth, Georg, Mitchell, Braxton D., Gudnason, Vilmundur, and O’Donnell, Christopher J.

Published
2019
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