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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Title: Mutant Induced Pluripotent Stem Cell Lines Recapitulate Aspects of TDP-43 Proteinopathies and Reveal Specific Vulnerability
Author: 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.; Daley, George Quentin; Wyllie, D. J. A.; Hardingham, G. E.; Finkbeiner, S.; Wilmut, I.; Finkbeiner, S.; Maniatis, Thomas P.

Note: Order does not necessarily reflect citation order of authors.

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.
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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.
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:8296379

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  • FAS Scholarly Articles [6929]
    Peer reviewed scholarly articles from the Faculty of Arts and Sciences of Harvard University
 
 

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