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
| 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. |
| Access Status: | At the direction of the depositing author this work is not currently accessible through DASH. |
| Full Text & Related Files: |
Friedman_mutant_dark.pdf (192.5Kb; PDF) 
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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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Peer reviewed scholarly articles from the Faculty of Arts and Sciences of Harvard University
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