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Cell Stem Cell DOI:10.1016/j.stem.2014.03.004

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

Publication TypeJournal Article
Year of Publication2014
AuthorsKiskinis, 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, J Joung, K, Woolf, CJ, Brown, RH, Eggan, K
JournalCell Stem Cell
Date Published2014 Jun 05
KeywordsAmyotrophic Lateral Sclerosis, Humans, Motor Neurons, Mutation, Superoxide Dismutase, Superoxide Dismutase-1

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.


Alternate JournalCell Stem Cell
PubMed ID24704492
PubMed Central IDPMC4653065
Grant ListDP1 GM105378 / GM / NIGMS NIH HHS / United States
RC2 NS069395 / NS / NINDS NIH HHS / United States
1U24NS078736-01 / NS / NINDS NIH HHS / United States
RC2 NS070342 / NS / NINDS NIH HHS / United States
OD006862 / OD / NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
DP1 OD006862 / OD / NIH HHS / United States
RC2-NS070-342 / NS / NINDS NIH HHS / United States
1R01NS050557 / NS / NINDS NIH HHS / United States
U24 NS078736 / NS / NINDS NIH HHS / United States
R00 NS077435 / NS / NINDS NIH HHS / United States
R01 NS050557 / NS / NINDS NIH HHS / United States
5RC2NS069395-02 / NS / NINDS NIH HHS / United States