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

Serio, Andrea; Bilican, Bilada; Barmada, Sami J.; Ando, Dale Michael; Zhao, Chen; Siller, Rick; Burr, Karen; Haghi, Ghazal; Story, David; Nishimura, Agnes Lumi; Carrasco, Monica A.; Phatnani, Hemali P.; Shum, Carole; Wilmut, Ian; Maniatis, Tom; Shaw, Christopher E.; Finkbeiner, Steven; Chandran, Siddharthan

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.


Also Published In

Proceedings of the National Academy of Sciences

More About This Work

Academic Units
Biochemistry and Molecular Biophysics
Published Here
May 8, 2013