title: Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy.
abstract: Glial proliferation and activation are associated with disease progression in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia. In this study, we describe a unique platform to address the question of cell autonomy in transactive response DNA-binding protein (TDP-43) proteinopathies. We generated functional astroglia from human induced pluripotent stem cells carrying an ALS-causing TDP-43 mutation and show that mutant astrocytes exhibit increased levels of TDP-43, subcellular mislocalization of TDP-43, and decreased cell survival. We then performed coculture experiments to evaluate the effects of M337V astrocytes on the survival of wild-type and M337V TDP-43 motor neurons, showing that mutant TDP-43 astrocytes do not adversely affect survival of cocultured neurons. These observations reveal a significant and previously unrecognized glial cell-autonomous pathological phenotype associated with a pathogenic mutation in TDP-43 and show that TDP-43 proteinopathies do not display an astrocyte non-cell-autonomous component in cell culture, as previously described for SOD1 ALS. This study highlights the utility of induced pluripotent stem cell-based in vitro disease models to investigate mechanisms of disease in ALS and other TDP-43 proteinopathies.
authors: Euan MacDonald Centre for Motor Neurone Disease Research, Centre for Neuroregeneration, and Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom.
authors: Andrea
authors: A
authors: Serio
authors: Bilada
authors: B
authors: Bilican
authors: Sami J
authors: SJ
authors: Barmada
authors: Dale Michael
authors: DM
authors: Ando
authors: Chen
authors: C
authors: Zhao
authors: Rick
authors: R
authors: Siller
authors: Karen
authors: K
authors: Burr
authors: Ghazal
authors: G
authors: Haghi
authors: David
authors: D
authors: Story
authors: Agnes Lumi
authors: AL
authors: Nishimura
authors: Monica A
authors: MA
authors: Carrasco
authors: Hemali P
authors: HP
authors: Phatnani
authors: Carole
authors: C
authors: Shum
authors: Ian
authors: I
authors: Wilmut
authors: Tom
authors: T
authors: Maniatis
authors: Christopher E
authors: CE
authors: Shaw
authors: Steven
authors: S
authors: Finkbeiner
authors: Siddharthan
authors: S
authors: Chandran
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009154:Mutation
chemical_list: D004268:DNA-Binding Proteins
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