Mutant Induced Pluripotent Stem Cell Lines Recapitulate Aspects of TDP-43 Proteinopathies and Reveal Specific Vulnerability

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Mutant Induced Pluripotent Stem Cell Lines Recapitulate Aspects of TDP-43 Proteinopathies and Reveal Specific Vulnerability

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dc.contributor.author Shaw, Christopher E.
dc.contributor.author Chandran, Siddharthan
dc.contributor.author Bilican, B.
dc.contributor.author Serio, A.
dc.contributor.author Barmada, S. J.
dc.contributor.author Nishimura, A. L.
dc.contributor.author Sullivan, G. J.
dc.contributor.author Carrasco, M.
dc.contributor.author Phatnani, P.
dc.contributor.author Friedman, Brad A.
dc.contributor.author Puddifoot, C. A.
dc.contributor.author Story, D.
dc.contributor.author Fletcher, J.
dc.contributor.author Park, I. H.
dc.contributor.author Daley, George Quentin
dc.contributor.author Wyllie, D. J. A.
dc.contributor.author Hardingham, G. E.
dc.contributor.author Finkbeiner, S.
dc.contributor.author Wilmut, I.
dc.contributor.author Finkbeiner, S.
dc.contributor.author Maniatis, Thomas P.
dc.date.accessioned 2012-03-01T15:13:12Z
dc.date.issued 2012
dc.identifier.citation Bilican, B., A. Serio, S. J. Barmada, A. L. Nishimura, G. J. Sullivan, M. Carrasco, H. P. Phatnani et alia. Forthcoming. Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal specific vulnerability. Proceedings of the National Academy of Sciences 109. en_US
dc.identifier.issn 1091-6490 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:8296379
dc.description.abstract Transactive response DNA-binding (TDP-43) protein is the dominant disease protein in amyotrophic lateral sclerosis (ALS) and a sub-group of frontotemporal lobar degeneration (FTLD-TDP). Identification of TARDBP mutations in familial ALS confirms a mechanistic link between misaccumulation of TDP-43 and neurodegeneration and provides an opportunity to study TDP-43 proteinopathies in human neurons generated from patient fibroblasts using induced pluripotent stem cells (iPSC). Here, we report the generation of iPSCs that carry the TDP-43 M337V mutation, and their differentiation into neurons and functional motor neurons. Mutant neurons had elevated levels of soluble and detergent- resistant TDP-43 protein, decreased survival in longitudinal studies, and increased vulnerability to antagonism of the phosphoinositide 3-kinase pathway. We conclude that expression of physiological levels of TDP-43 in human neurons is sufficient to reveal a mutation-specific cell autonomous phenotype and strongly supports this approach for the study of disease mechanisms and for drug screening. en_US
dc.description.sponsorship Molecular and Cellular Biology en_US
dc.language.iso en_US en_US
dc.publisher National Academy of Sciences en_US
dash.license META_ONLY
dc.title Mutant Induced Pluripotent Stem Cell Lines Recapitulate Aspects of TDP-43 Proteinopathies and Reveal Specific Vulnerability en_US
dc.type Journal Article en_US
dc.description.version Accepted Manuscript en_US
dc.relation.journal Proceedings of the National Academy of Sciences en_US
dash.depositing.author Maniatis, Thomas P.
dash.embargo.until 10000-01-01
dash.waiver 2012-02-29

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  • FAS Scholarly Articles [6463]
    Peer reviewed scholarly articles from the Faculty of Arts and Sciences of Harvard University

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