Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability

Bilada Bilican; Andrea Serio; Sami J. Barmada; Agnes Lumi Nishimura; Gareth J. Sullivan; Monica Carrasco; Hemali P. Phatnani; Clare A. Puddifoot; David Story; Judy Fletcher; In-Hyun Park; Brad A. Friedman; George Q. Daley; David J. A. Wyllie; Giles E. Hardingham; Ian Wilmut; Steven Finkbeiner; Tom Maniatis; Christopher E. Shaw; Siddharthan Chandran

doi:10.1073/pnas.1202922109

Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability

Bilada Bilican, Andrea Serio, Sami J. Barmada, Agnes Lumi Nishimura, Gareth J. Sullivan, Monica Carrasco, Hemali P. Phatnani, Clare A. Puddifoot, David Story, Judy Fletcher, In-Hyun Park, Brad A. Friedman, George Q. Daley, David J. A. Wyllie, Giles E. Hardingham, Ian Wilmut, Steven Finkbeiner, Tom Maniatis, Christopher E. Shaw, Siddharthan Chandran

Research output: Contribution to journal › Article › peer-review

273 Citations (Scopus)

Abstract

Transactive response DNA-binding (TDP-43) protein is the dominant disease protein in amyotrophic lateral sclerosis (ALS) and a subgroup of frontotemporal lobar degeneration (FTLD-TDP). Identification of mutations in the gene encoding TDP-43 (TARDBP) in familial ALS confirms a mechanistic link between misaccumulation of TDP-43 and neurodegeneration and provides an opportunity to study TDP-43 proteinopathies in human neurons generated from patient fibroblasts by using induced pluripotent stem cells (iPSCs). Here, we report the generation of iPSCs that carry the TDP-43 M337V mutation and their differentiation into neurons and functional motor neurons. Mutant neurons had elevated levels of soluble and detergent-resistant TDP-43 protein, decreased survival in longitudinal studies, and increased vulnerability to antagonism of the PI3K pathway. We conclude that expression of physiological levels of TDP-43 in human neurons is sufficient to reveal a mutation-specific cell-autonomous phenotype and strongly supports this approach for the study of disease mechanisms and for drug screening.

Original language	English
Pages (from-to)	5803 - 5808
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	109
Issue number	15
DOIs	https://doi.org/10.1073/pnas.1202922109
Publication status	Published - 10 Apr 2012

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Bilican, B., Serio, A., Barmada, S. J., Nishimura, A. L., Sullivan, G. J., Carrasco, M., Phatnani, H. P., Puddifoot, C. A., Story, D., Fletcher, J., Park, I.-H., Friedman, B. A., Daley, G. Q., Wyllie, D. J. A., Hardingham, G. E., Wilmut, I., Finkbeiner, S., Maniatis, T., Shaw, C. E., & Chandran, S. (2012). Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proceedings of the National Academy of Sciences of the United States of America, 109(15), 5803 - 5808. https://doi.org/10.1073/pnas.1202922109

@article{747a271b24a94b7dacab57d31fad1ad7,

title = "Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability",

abstract = "Transactive response DNA-binding (TDP-43) protein is the dominant disease protein in amyotrophic lateral sclerosis (ALS) and a subgroup of frontotemporal lobar degeneration (FTLD-TDP). Identification of mutations in the gene encoding TDP-43 (TARDBP) in familial ALS confirms a mechanistic link between misaccumulation of TDP-43 and neurodegeneration and provides an opportunity to study TDP-43 proteinopathies in human neurons generated from patient fibroblasts by using induced pluripotent stem cells (iPSCs). Here, we report the generation of iPSCs that carry the TDP-43 M337V mutation and their differentiation into neurons and functional motor neurons. Mutant neurons had elevated levels of soluble and detergent-resistant TDP-43 protein, decreased survival in longitudinal studies, and increased vulnerability to antagonism of the PI3K pathway. We conclude that expression of physiological levels of TDP-43 in human neurons is sufficient to reveal a mutation-specific cell-autonomous phenotype and strongly supports this approach for the study of disease mechanisms and for drug screening.",

author = "Bilada Bilican and Andrea Serio and Barmada, {Sami J.} and Nishimura, {Agnes Lumi} and Sullivan, {Gareth J.} and Monica Carrasco and Phatnani, {Hemali P.} and Puddifoot, {Clare A.} and David Story and Judy Fletcher and In-Hyun Park and Friedman, {Brad A.} and Daley, {George Q.} and Wyllie, {David J. A.} and Hardingham, {Giles E.} and Ian Wilmut and Steven Finkbeiner and Tom Maniatis and Shaw, {Christopher E.} and Siddharthan Chandran",

year = "2012",

month = apr,

day = "10",

doi = "10.1073/pnas.1202922109",

language = "English",

volume = "109",

pages = "5803 -- 5808",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "1091-6490",

publisher = "National Acad Sciences",

number = "15",

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Bilican, B, Serio, A, Barmada, SJ, Nishimura, AL, Sullivan, GJ, Carrasco, M, Phatnani, HP, Puddifoot, CA, Story, D, Fletcher, J, Park, I-H, Friedman, BA, Daley, GQ, Wyllie, DJA, Hardingham, GE, Wilmut, I, Finkbeiner, S, Maniatis, T, Shaw, CE & Chandran, S 2012, 'Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 15, pp. 5803 - 5808. https://doi.org/10.1073/pnas.1202922109

Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. / Bilican, Bilada; Serio, Andrea; Barmada, Sami J. et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 15, 10.04.2012, p. 5803 - 5808.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability

AU - Bilican, Bilada

AU - Serio, Andrea

AU - Barmada, Sami J.

AU - Nishimura, Agnes Lumi

AU - Sullivan, Gareth J.

AU - Carrasco, Monica

AU - Phatnani, Hemali P.

AU - Puddifoot, Clare A.

AU - Story, David

AU - Fletcher, Judy

AU - Park, In-Hyun

AU - Friedman, Brad A.

AU - Daley, George Q.

AU - Wyllie, David J. A.

AU - Hardingham, Giles E.

AU - Wilmut, Ian

AU - Finkbeiner, Steven

AU - Maniatis, Tom

AU - Shaw, Christopher E.

AU - Chandran, Siddharthan

PY - 2012/4/10

Y1 - 2012/4/10

N2 - Transactive response DNA-binding (TDP-43) protein is the dominant disease protein in amyotrophic lateral sclerosis (ALS) and a subgroup of frontotemporal lobar degeneration (FTLD-TDP). Identification of mutations in the gene encoding TDP-43 (TARDBP) in familial ALS confirms a mechanistic link between misaccumulation of TDP-43 and neurodegeneration and provides an opportunity to study TDP-43 proteinopathies in human neurons generated from patient fibroblasts by using induced pluripotent stem cells (iPSCs). Here, we report the generation of iPSCs that carry the TDP-43 M337V mutation and their differentiation into neurons and functional motor neurons. Mutant neurons had elevated levels of soluble and detergent-resistant TDP-43 protein, decreased survival in longitudinal studies, and increased vulnerability to antagonism of the PI3K pathway. We conclude that expression of physiological levels of TDP-43 in human neurons is sufficient to reveal a mutation-specific cell-autonomous phenotype and strongly supports this approach for the study of disease mechanisms and for drug screening.

AB - Transactive response DNA-binding (TDP-43) protein is the dominant disease protein in amyotrophic lateral sclerosis (ALS) and a subgroup of frontotemporal lobar degeneration (FTLD-TDP). Identification of mutations in the gene encoding TDP-43 (TARDBP) in familial ALS confirms a mechanistic link between misaccumulation of TDP-43 and neurodegeneration and provides an opportunity to study TDP-43 proteinopathies in human neurons generated from patient fibroblasts by using induced pluripotent stem cells (iPSCs). Here, we report the generation of iPSCs that carry the TDP-43 M337V mutation and their differentiation into neurons and functional motor neurons. Mutant neurons had elevated levels of soluble and detergent-resistant TDP-43 protein, decreased survival in longitudinal studies, and increased vulnerability to antagonism of the PI3K pathway. We conclude that expression of physiological levels of TDP-43 in human neurons is sufficient to reveal a mutation-specific cell-autonomous phenotype and strongly supports this approach for the study of disease mechanisms and for drug screening.

U2 - 10.1073/pnas.1202922109

DO - 10.1073/pnas.1202922109

M3 - Article

SN - 1091-6490

VL - 109

SP - 5803

EP - 5808

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 - 15

ER -

Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability

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