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

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 reprogrammi...

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Bibliographic Details
Published in:	Cell stem cell Vol. 14; no. 6; p. 781
Main Authors:	Kiskinis, Evangelos, Sandoe, Jackson, Williams, Luis A, Boulting, Gabriella L, Moccia, Rob, Wainger, Brian J, Han, Steve, Peng, Theodore, Thams, Sebastian, Mikkilineni, Shravani, Mellin, Cassidy, Merkle, Florian T, Davis-Dusenbery, Brandi N, Ziller, Michael, Oakley, Derek, Ichida, Justin, Di Costanzo, Stefania, Atwater, Nick, Maeder, Morgan L, Goodwin, Mathew J, Nemesh, James, Handsaker, Robert E, Paull, Daniel, Noggle, Scott, McCarroll, Steven A, Joung, J Keith, Woolf, Clifford J, Brown, Robert H, Eggan, Kevin
Format:	Journal Article
Language:	English
Published:	United States 05.06.2014
Subjects:	Amyotrophic Lateral Sclerosis - genetics Amyotrophic Lateral Sclerosis - metabolism Amyotrophic Lateral Sclerosis - pathology Humans Motor Neurons - metabolism Motor Neurons - pathology Mutation Superoxide Dismutase - genetics Superoxide Dismutase - metabolism Superoxide Dismutase-1
ISSN:	1875-9777, 1875-9777
Online Access:	Get more information
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3
ISSN:	1875-9777 1875-9777
DOI:	10.1016/j.stem.2014.03.004