Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability
Year: 2012
Type: article
Abstract: Transactive response DNA-binding (TDP-43) protein is the dominant disease protein in amyotrophic lateral sclerosis (ALS) and a subgroup of frontotemporal lobar degeneration (FTLD-TDP). Identification of mutations in the gene encoding TDP-43 (TARDBP) 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 by using induced pluripotent stem cells (iPSCs). 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 PI3K 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.
Authors: Bilada Bilican, Andrea Serio, Sami J. Barmada, Agnes Lumi Nishimura, Gareth J. Sullivan, Monica Carrasco, Hemali P. Phatnani, Clare A. Puddifoot, David Story, Judy Fletcher, In-Hyun Park, Brad A. Friedman, George Q. Daley, David J. A. Wyllie, Giles E. Hardingham, Ian Wilmut, Steven Finkbeiner, Tom Maniatis, Christopher E. Shaw, Siddharthan Chandran
Institutions: MRC Centre for Regenerative Medicine, Euan MacDonald Centre for Motor Neuron Disease Research, Medical Research Council, University of Edinburgh, Gladstone Institutes, University of California, San Francisco, Taube Koret Center, King's College London, Columbia University, Yale University, Harvard University, Harvard Stem Cell Institute
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: RNA processing proteins and neurodegeneration: exploring mechanisms and modelling disease, G3899333775, Elucidating the Mechanisms Underlying Mutant TDP43-induced Neurodegeneration, RNA processing proteins and neurodegeneration: exploring mechanisms and modelling disease., Mechanisms of Huntingtin-induced Neurodegeneration, G5464234346
OpenAlex ID: W2131321387