Journal Article

Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability

Serio, Andrea, Barmada, Sami J, Puddifoot, Clare A, Maniatis, Tom, Finkbeiner, Steven, Wilmut, Ian, Carrasco, Monica, Wyllie, David J. A, Hardingham, Giles E, Phatnani, Hemali P, Fletcher, Judy, Friedman, Brad A, Bilican, Bilada, Shaw, Christopher E, Park, In-Hyun, Nishimura, Agnes Lumi, Story, David, Daley, George Q, Chandran, Siddharthan, Sullivan, Gareth J

2012

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Adult / Amyotrophic lateral sclerosis / Binding sites / Biological Sciences / Cell Differentiation / Cell Differentiation - drug effects / Cell lines / Detergents / Detergents - pharmacology / Disease models / DNA-Binding Proteins / DNA-Binding Proteins - metabolism / drug effects / drugs / Female / fibroblasts / Fibroblasts - drug effects / Fibroblasts - metabolism / Fibroblasts - pathology / genes / Genetic mutation / genetics / Humans / Induced Pluripotent Stem Cells / Induced Pluripotent Stem Cells - drug effects / Induced Pluripotent Stem Cells - metabolism / Longitudinal studies / Male / metabolism / Middle Aged / Motor neurons / Motor Neurons - drug effects / Motor Neurons - metabolism / Motor Neurons - pathology / mutants / Mutation / Mutation - genetics / Nervous system diseases / Neurodegenerative diseases / Neurons / Organ Specificity / Organ Specificity - drug effects / pathology / patients / pharmacology / phenotype / phosphatidylinositol 3-kinase / Proteins / sclerosis / screening / Solubility / Solubility - drug effects / Stem cells / TDP-43 Proteinopathies / TDP-43 Proteinopathies - genetics