Mutant Induced Pluripotent Stem Cell Lines Recapitulate Aspects of TDP-43 Proteinopathies and Reveal Specific Vulnerability
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Shaw, Christopher E.
Chandran, Siddharthan
Bilican, B.
Serio, A.
Barmada, S. J.
Nishimura, A. L.
Sullivan, G. J.
Carrasco, M.
Phatnani, P.
Friedman, Brad A.
Puddifoot, C. A.
Story, D.
Fletcher, J.
Park, I. H.
Wyllie, D. J. A.
Hardingham, G. E.
Finkbeiner, S.
Wilmut, I.
Finkbeiner, S.
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1073/pnas.1202922109Metadata
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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.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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326463/Citable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:8296379
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