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

TY - JOUR

T1 - Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy

AU - Serio, Andrea

AU - Bilican, Bilada

AU - Barmada, Sami J.

AU - Ando, Dale Michael

AU - Zhao, Chen

AU - Siller, Rick

AU - Burr, Karen

AU - Haghi, Ghazal

AU - Story, David

AU - Nishimura, Agnes Lumi

AU - Carrasco, Monica A.

AU - Phatnani, Hemali P.

AU - Shum, Carole

AU - Wilmut, Ian

AU - Maniatis, Tom

AU - Shaw, Christopher E.

AU - Finkbeiner, Steven

AU - Chandran, Siddharthan

PY - 2013/3/19

Y1 - 2013/3/19

N2 - 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.

AB - 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.

KW - MUTANT SOD1

KW - motor neuron disease

KW - disease modeling

KW - FRONTOTEMPORAL LOBAR DEGENERATION

KW - glia

KW - PRECURSOR CELLS

KW - PATHWAY

KW - DIFFERENTIATION

KW - ASTROGLIOSIS

KW - AMYOTROPHIC-LATERAL-SCLEROSIS

KW - MOTOR-NEURONS

KW - SPINAL-CORD

KW - DISEASE

U2 - 10.1073/pnas.1300398110

DO - 10.1073/pnas.1300398110

M3 - Article

SN - 0027-8424

VL - 110

SP - 4697

EP - 4702

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 12

ER -