title: Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability.
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.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Bilada
authors.initials: B
authors.lastname: Bilican
authors.forename: Andrea
authors.initials: A
authors.lastname: Serio
authors.forename: Sami J
authors.initials: SJ
authors.lastname: Barmada
authors.forename: Agnes Lumi
authors.initials: AL
authors.lastname: Nishimura
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Sullivan
authors.forename: Monica
authors.initials: M
authors.lastname: Carrasco
authors.forename: Hemali P
authors.initials: HP
authors.lastname: Phatnani
authors.forename: Clare A
authors.initials: CA
authors.lastname: Puddifoot
authors.forename: David
authors.initials: D
authors.lastname: Story
authors.forename: Judy
authors.initials: J
authors.lastname: Fletcher
authors.forename: In-Hyun
authors.initials: IH
authors.lastname: Park
authors.forename: Brad A
authors.initials: BA
authors.lastname: Friedman
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.forename: David J A
authors.initials: DJ
authors.lastname: Wyllie
authors.forename: Giles E
authors.initials: GE
authors.lastname: Hardingham
authors.forename: Ian
authors.initials: I
authors.lastname: Wilmut
authors.forename: Steven
authors.initials: S
authors.lastname: Finkbeiner
authors.forename: Tom
authors.initials: T
authors.lastname: Maniatis
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: Siddharthan
authors.initials: S
authors.lastname: Chandran
mesh_terms: D000328:Adult; D002454:Cell Differentiation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D009928:Organ Specificity / Q000187:drug effects; D012995:Solubility / Q000187:drug effects; D057177:TDP-43 Proteinopathies / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D003902:Detergents