Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 15, Pages 5803-5808Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1202922109
Keywords
disease modeling; reprogramming; motor neuron disease; Lou Gehrig disease
Categories
Funding
- Euan MacDonald Centre
- Fidelity Foundation
- Motor Neurone Disease Association
- Medical Research Council
- Wellcome Trust
- Heaton-Ellis Trust
- BBSRC
- ALS Association
- Rodenberry Stem Cell Program
- Hellman Family Foundation
- National Institutes of Neurological Disease and Stroke
- National Institutes on Aging
- MRC [G0300329, G0900688, MC_G1000733, G0902044, G0500289] Funding Source: UKRI
- Medical Research Council [G0500289B, G0900688, MC_G1000733, G0300329, G0902044, G0700711B, G0500289] Funding Source: researchfish
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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.
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