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Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy

OPEN Proceedings of the National Academy of Sciences of the United States of America | 13 Feb 2013

A Serio, B Bilican, SJ Barmada, DM Ando, C Zhao, R Siller, K Burr, G Haghi, D Story, AL Nishimura, MA Carrasco, HP Phatnani, C Shum, I Wilmut, T Maniatis, CE Shaw, S Finkbeiner and S Chandran
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.
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Developmental biology, DNA, Pluripotency, Stem cells, Amyotrophic lateral sclerosis, Cell biology, Induced pluripotent stem cell, Stem cell
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