Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1

Evangelos Kiskinis; Jackson Sandoe; Luis A. Williams; Gabriella L. Boulting; Rob Moccia; Brian J. Wainger; Steve Han; Theodore Peng; Sebastian Thams; Shravani Mikkilineni; Cassidy Mellin; Florian T. Merkle; Brandi N. Davis-Dusenbery; Michael Ziller; Derek Oakley; Justin Ichida; Stefania Di Costanzo; Nick Atwater; Morgan L. Maeder; Mathew J. Goodwin; James Nemesh; Robert E. Handsaker; Daniel Paull; Scott Noggle; Steven A. McCarroll; J. Keith Joung; Clifford J. Woolf; Robert H. Brown; Kevin Eggan

doi:10.1016/j.stem.2014.03.004

Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1

Evangelos Kiskinis, Jackson Sandoe, Luis A. Williams, Gabriella L. Boulting, Rob Moccia, Brian J. Wainger, Steve Han, Theodore Peng, Sebastian Thams, Shravani Mikkilineni, Cassidy Mellin, Florian T. Merkle, Brandi N. Davis-Dusenbery, Michael Ziller, Derek Oakley, Justin Ichida, Stefania Di Costanzo, Nick Atwater, Morgan L. Maeder, Mathew J. GoodwinJames Nemesh, Robert E. Handsaker, Daniel Paull, Scott Noggle, Steven A. McCarroll, J. Keith Joung, Clifford J. Woolf, Robert H. Brown, Kevin Eggan^*

^*Corresponding author for this work

Neurology

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

296 Scopus citations

Abstract

Although many distinct mutations in a variety of genes are known to cause Amyotrophic Lateral Sclerosis (ALS), it remains poorly understood how they selectively impact motor neuron biology and whether they converge on common pathways to cause neuronal degeneration. Here, we have combined reprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing to define the transcriptional and functional changes that are induced in human motor neurons by mutant SOD1. Mutant SOD1 protein induced a transcriptional signature indicative of increased oxidative stress, reduced mitochondrial function, altered subcellular transport, and activation of the ER stress and unfolded protein response pathways. Functional studies demonstrated that these pathways were perturbed in a manner dependent on the SOD1 mutation. Finally, interrogation of stem-cell-derived motor neurons produced from ALS patients harboring a repeat expansion in C9orf72 indicates that at least a subset of these changes are more broadly conserved in ALS.

Original language	English (US)
Pages (from-to)	781-795
Number of pages	15
Journal	Cell stem cell
Volume	14
Issue number	6
DOIs	https://doi.org/10.1016/j.stem.2014.03.004
State	Published - Jun 5 2014

Funding

We thank H. Mitsumoto and D. McKenna-Yasek for performing skin biopsies; K. Koszka for maintaining mice; all members of the Eggan Lab; and C. Henderson and M.W. Amoroso for helpful comments on the manuscript. R.H.B. acknowledges generous support from the ALS Therapy Alliance, Project ALS, P2ALS, the Angel Fund, the Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Research Foundation, the ALS Family Charitable Foundation, and the NIH/NINDS (1R01NS050557 and NINDS ARRA Award RC2-NS070-342). This work was funded by Target ALS, Project A.L.S., P2ALS, NINDS GO grant (5RC2NS069395-02), NINDS R24 (1U24NS078736-01), the HHMI, and the NIH Director’s Pioneer Award DP1 (OD006862). E.K. is a Charles A. King Trust Postdoctoral fellow, and K.E. is an HHMI early career scientist. J.K.J. has financial interests in Editas Medicine and Transposagen Biopharmaceuticals. J.K.J.'s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies.

ASJC Scopus subject areas

Genetics
Molecular Medicine
Cell Biology

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Kiskinis, E., Sandoe, J., Williams, L. A., Boulting, G. L., Moccia, R., Wainger, B. J., Han, S., Peng, T., Thams, S., Mikkilineni, S., Mellin, C., Merkle, F. T., Davis-Dusenbery, B. N., Ziller, M., Oakley, D., Ichida, J., Di Costanzo, S., Atwater, N., Maeder, M. L., ... Eggan, K. (2014). Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1. Cell stem cell, 14(6), 781-795. https://doi.org/10.1016/j.stem.2014.03.004

@article{8e1ddd8bfb15457eaaff40161bf48ee5,

title = "Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1",

abstract = "Although many distinct mutations in a variety of genes are known to cause Amyotrophic Lateral Sclerosis (ALS), it remains poorly understood how they selectively impact motor neuron biology and whether they converge on common pathways to cause neuronal degeneration. Here, we have combined reprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing to define the transcriptional and functional changes that are induced in human motor neurons by mutant SOD1. Mutant SOD1 protein induced a transcriptional signature indicative of increased oxidative stress, reduced mitochondrial function, altered subcellular transport, and activation of the ER stress and unfolded protein response pathways. Functional studies demonstrated that these pathways were perturbed in a manner dependent on the SOD1 mutation. Finally, interrogation of stem-cell-derived motor neurons produced from ALS patients harboring a repeat expansion in C9orf72 indicates that at least a subset of these changes are more broadly conserved in ALS.",

author = "Evangelos Kiskinis and Jackson Sandoe and Williams, {Luis A.} and Boulting, {Gabriella L.} and Rob Moccia and Wainger, {Brian J.} and Steve Han and Theodore Peng and Sebastian Thams and Shravani Mikkilineni and Cassidy Mellin and Merkle, {Florian T.} and Davis-Dusenbery, {Brandi N.} and Michael Ziller and Derek Oakley and Justin Ichida and {Di Costanzo}, Stefania and Nick Atwater and Maeder, {Morgan L.} and Goodwin, {Mathew J.} and James Nemesh and Handsaker, {Robert E.} and Daniel Paull and Scott Noggle and McCarroll, {Steven A.} and Joung, {J. Keith} and Woolf, {Clifford J.} and Brown, {Robert H.} and Kevin Eggan",

note = "Funding Information: We thank H. Mitsumoto and D. McKenna-Yasek for performing skin biopsies; K. Koszka for maintaining mice; all members of the Eggan Lab; and C. Henderson and M.W. Amoroso for helpful comments on the manuscript. R.H.B. acknowledges generous support from the ALS Therapy Alliance, Project ALS, P2ALS, the Angel Fund, the Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Research Foundation, the ALS Family Charitable Foundation, and the NIH/NINDS (1R01NS050557 and NINDS ARRA Award RC2-NS070-342). This work was funded by Target ALS, Project A.L.S., P2ALS, NINDS GO grant (5RC2NS069395-02), NINDS R24 (1U24NS078736-01), the HHMI, and the NIH Director{\textquoteright}s Pioneer Award DP1 (OD006862). E.K. is a Charles A. King Trust Postdoctoral fellow, and K.E. is an HHMI early career scientist. J.K.J. has financial interests in Editas Medicine and Transposagen Biopharmaceuticals. J.K.J.'s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. ",

year = "2014",

month = jun,

day = "5",

doi = "10.1016/j.stem.2014.03.004",

language = "English (US)",

volume = "14",

pages = "781--795",

journal = "Cell stem cell",

issn = "1934-5909",

publisher = "Cell Press",

number = "6",

}

Kiskinis, E, Sandoe, J, Williams, LA, Boulting, GL, Moccia, R, Wainger, BJ, Han, S, Peng, T, Thams, S, Mikkilineni, S, Mellin, C, Merkle, FT, Davis-Dusenbery, BN, Ziller, M, Oakley, D, Ichida, J, Di Costanzo, S, Atwater, N, Maeder, ML, Goodwin, MJ, Nemesh, J, Handsaker, RE, Paull, D, Noggle, S, McCarroll, SA, Joung, JK, Woolf, CJ, Brown, RH & Eggan, K 2014, 'Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1', Cell stem cell, vol. 14, no. 6, pp. 781-795. https://doi.org/10.1016/j.stem.2014.03.004

TY - JOUR

T1 - Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1

AU - Kiskinis, Evangelos

AU - Sandoe, Jackson

AU - Williams, Luis A.

AU - Boulting, Gabriella L.

AU - Moccia, Rob

AU - Wainger, Brian J.

AU - Han, Steve

AU - Peng, Theodore

AU - Thams, Sebastian

AU - Mikkilineni, Shravani

AU - Mellin, Cassidy

AU - Merkle, Florian T.

AU - Davis-Dusenbery, Brandi N.

AU - Ziller, Michael

AU - Oakley, Derek

AU - Ichida, Justin

AU - Di Costanzo, Stefania

AU - Atwater, Nick

AU - Maeder, Morgan L.

AU - Goodwin, Mathew J.

AU - Nemesh, James

AU - Handsaker, Robert E.

AU - Paull, Daniel

AU - Noggle, Scott

AU - McCarroll, Steven A.

AU - Joung, J. Keith

AU - Woolf, Clifford J.

AU - Brown, Robert H.

AU - Eggan, Kevin

N1 - Funding Information: We thank H. Mitsumoto and D. McKenna-Yasek for performing skin biopsies; K. Koszka for maintaining mice; all members of the Eggan Lab; and C. Henderson and M.W. Amoroso for helpful comments on the manuscript. R.H.B. acknowledges generous support from the ALS Therapy Alliance, Project ALS, P2ALS, the Angel Fund, the Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Research Foundation, the ALS Family Charitable Foundation, and the NIH/NINDS (1R01NS050557 and NINDS ARRA Award RC2-NS070-342). This work was funded by Target ALS, Project A.L.S., P2ALS, NINDS GO grant (5RC2NS069395-02), NINDS R24 (1U24NS078736-01), the HHMI, and the NIH Director’s Pioneer Award DP1 (OD006862). E.K. is a Charles A. King Trust Postdoctoral fellow, and K.E. is an HHMI early career scientist. J.K.J. has financial interests in Editas Medicine and Transposagen Biopharmaceuticals. J.K.J.'s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies.

PY - 2014/6/5

Y1 - 2014/6/5

N2 - Although many distinct mutations in a variety of genes are known to cause Amyotrophic Lateral Sclerosis (ALS), it remains poorly understood how they selectively impact motor neuron biology and whether they converge on common pathways to cause neuronal degeneration. Here, we have combined reprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing to define the transcriptional and functional changes that are induced in human motor neurons by mutant SOD1. Mutant SOD1 protein induced a transcriptional signature indicative of increased oxidative stress, reduced mitochondrial function, altered subcellular transport, and activation of the ER stress and unfolded protein response pathways. Functional studies demonstrated that these pathways were perturbed in a manner dependent on the SOD1 mutation. Finally, interrogation of stem-cell-derived motor neurons produced from ALS patients harboring a repeat expansion in C9orf72 indicates that at least a subset of these changes are more broadly conserved in ALS.

AB - Although many distinct mutations in a variety of genes are known to cause Amyotrophic Lateral Sclerosis (ALS), it remains poorly understood how they selectively impact motor neuron biology and whether they converge on common pathways to cause neuronal degeneration. Here, we have combined reprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing to define the transcriptional and functional changes that are induced in human motor neurons by mutant SOD1. Mutant SOD1 protein induced a transcriptional signature indicative of increased oxidative stress, reduced mitochondrial function, altered subcellular transport, and activation of the ER stress and unfolded protein response pathways. Functional studies demonstrated that these pathways were perturbed in a manner dependent on the SOD1 mutation. Finally, interrogation of stem-cell-derived motor neurons produced from ALS patients harboring a repeat expansion in C9orf72 indicates that at least a subset of these changes are more broadly conserved in ALS.

UR - http://www.scopus.com/inward/record.url?scp=84902191691&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84902191691&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2014.03.004

DO - 10.1016/j.stem.2014.03.004

M3 - Article

C2 - 24704492

AN - SCOPUS:84902191691

SN - 1934-5909

VL - 14

SP - 781

EP - 795

JO - Cell stem cell

JF - Cell stem cell

IS - 6

ER -

Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1

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