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Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions.
Lam, Isabel; Ndayisaba, Alain; Lewis, Amanda J; Fu, YuHong; Sagredo, Giselle T; Kuzkina, Anastasia; Zaccagnini, Ludovica; Celikag, Meral; Sandoe, Jackson; Sanz, Ricardo L; Vahdatshoar, Aazam; Martin, Timothy D; Morshed, Nader; Ichihashi, Toru; Tripathi, Arati; Ramalingam, Nagendran; Oettgen-Suazo, Charlotte; Bartels, Theresa; Boussouf, Manel; Schäbinger, Max; Hallacli, Erinc; Jiang, Xin; Verma, Amrita; Tea, Challana; Wang, Zichen; Hakozaki, Hiroyuki; Yu, Xiao; Hyles, Kelly; Park, Chansaem; Wang, Xinyuan; Theunissen, Thorold W; Wang, Haoyi; Jaenisch, Rudolf; Lindquist, Susan; Stevens, Beth; Stefanova, Nadia; Wenning, Gregor; van de Berg, Wilma D J; Luk, Kelvin C; Sanchez-Pernaute, Rosario; Gómez-Esteban, Juan Carlos; Felsky, Daniel; Kiyota, Yasujiro; Sahni, Nidhi; Yi, S Stephen; Chung, Chee Yeun; Stahlberg, Henning; Ferrer, Isidro; Schöneberg, Johannes; Elledge, Stephen J.
Afiliação
  • Lam I; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; H
  • Ndayisaba A; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; H
  • Lewis AJ; École Polytechnique Fédérale de Lausanne and University of Lausanne, Lausanne, Switzerland.
  • Fu Y; The University of Sydney Brain and Mind Centre and Faculty of Medicine and Health School of Medical Science, Sydney, NSW, Australia.
  • Sagredo GT; The University of Sydney Brain and Mind Centre and Faculty of Medicine and Health School of Medical Science, Sydney, NSW, Australia.
  • Kuzkina A; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; H
  • Zaccagnini L; Dementia Research Institute, University College London, London, UK.
  • Celikag M; Dementia Research Institute, University College London, London, UK.
  • Sandoe J; Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
  • Sanz RL; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; H
  • Vahdatshoar A; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
  • Martin TD; Harvard Medical School, Boston, MA, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • Morshed N; Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA; Boston Children's Hospital, Boston, MA, USA; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ichihashi T; Nikon Corporation, Tokyo, Japan.
  • Tripathi A; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
  • Ramalingam N; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
  • Oettgen-Suazo C; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
  • Bartels T; Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
  • Boussouf M; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
  • Schäbinger M; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
  • Hallacli E; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; H
  • Jiang X; Yumanity Therapeutics, Cambridge, MA, USA.
  • Verma A; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
  • Tea C; University of California, San Diego, San Diego, CA, USA.
  • Wang Z; University of California, San Diego, San Diego, CA, USA.
  • Hakozaki H; University of California, San Diego, San Diego, CA, USA.
  • Yu X; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
  • Hyles K; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
  • Park C; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
  • Wang X; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; H
  • Theunissen TW; Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
  • Wang H; Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
  • Jaenisch R; Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
  • Lindquist S; Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • Stevens B; Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA; Boston Children's Hospital, Boston, MA, USA; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Stefanova N; Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
  • Wenning G; Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
  • van de Berg WDJ; Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, the Netherlands.
  • Luk KC; University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • Sanchez-Pernaute R; BioBizkaia Health Research Institute, Barakaldo, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
  • Gómez-Esteban JC; BioBizkaia Health Research Institute, Barakaldo, Spain.
  • Felsky D; Centre for Addiction and Mental Health, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada.
  • Kiyota Y; Nikon Corporation, Tokyo, Japan.
  • Sahni N; The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Baylor College of Medicine, Houston, TX, USA.
  • Yi SS; The University of Texas at Austin, Austin, TX, USA.
  • Chung CY; Yumanity Therapeutics, Cambridge, MA, USA.
  • Stahlberg H; École Polytechnique Fédérale de Lausanne and University of Lausanne, Lausanne, Switzerland.
  • Ferrer I; The University of Barcelona, Institut d'Investigacio Biomedica de Bellvitge IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
  • Schöneberg J; University of California, San Diego, San Diego, CA, USA.
  • Elledge SJ; Harvard Medical School, Boston, MA, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Neuron ; 112(17): 2886-2909.e16, 2024 Sep 04.
Article em En | MEDLINE | ID: mdl-39079530
ABSTRACT
The heterogeneity of protein-rich inclusions and its significance in neurodegeneration is poorly understood. Standard patient-derived iPSC models develop inclusions neither reproducibly nor in a reasonable time frame. Here, we developed screenable iPSC "inclusionopathy" models utilizing piggyBac or targeted transgenes to rapidly induce CNS cells that express aggregation-prone proteins at brain-like levels. Inclusions and their effects on cell survival were trackable at single-inclusion resolution. Exemplar cortical neuron α-synuclein inclusionopathy models were engineered through transgenic expression of α-synuclein mutant forms or exogenous seeding with fibrils. We identified multiple inclusion classes, including neuroprotective p62-positive inclusions versus dynamic and neurotoxic lipid-rich inclusions, both identified in patient brains. Fusion events between these inclusion subtypes altered neuronal survival. Proteome-scale α-synuclein genetic- and physical-interaction screens pinpointed candidate RNA-processing and actin-cytoskeleton-modulator proteins like RhoA whose sequestration into inclusions could enhance toxicity. These tractable CNS models should prove useful in functional genomic analysis and drug development for proteinopathies.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Corpos de Inclusão / Alfa-Sinucleína / Células-Tronco Pluripotentes Induzidas Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
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PubMed Links
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Corpos de Inclusão / Alfa-Sinucleína / Células-Tronco Pluripotentes Induzidas Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article