Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 12, Pages 4697-4702Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1300398110
Keywords
glia; motor neuron disease; disease modeling
Categories
Funding
- Euan MacDonald Centre
- Fidelity Foundation
- Motor Neurone Disease Association
- Medical Research Council
- Wellcome Trust
- Heaton-Ellis Trust
- ALS Association
- National Institutes of Neurological Disease and Stroke
- National Institutes on Aging
- National Institutes of Health [8DP1NS082099-06]
- MRC [MC_G1000733, G0300329, G0900688] Funding Source: UKRI
- Medical Research Council [G0300329, G0900688, MC_G1000733, G0700711B] Funding Source: researchfish
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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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