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

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

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)5803-5808
Number of pages6
JournalProceedings of the National Academy of Sciences (PNAS)
Volume109
Issue number15
DOIs
Publication statusPublished - 10 Apr 2012

Keywords / Materials (for Non-textual outputs)

  • disease modeling
  • reprogramming
  • motor neuron disease
  • Lou Gehrig disease

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