(National Academy of Sciences, 2012) 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; Wyllie, D. J. A.; Hardingham, G. E.; Finkbeiner, S.; Wilmut, I.; Maniatis, Thomas
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.
