Shaw, Christopher E.Chandran, SiddharthanBilican, 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, GeorgeWyllie, D. J. A.Hardingham, G. E.Finkbeiner, S.Wilmut, I.Maniatis, Thomas2012-03-012012Bilican, 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 109.1091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:8296379Transactive 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-USJournal Article10.1073/pnas.1202922109