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

Research output: Contribution to journalArticlepeer-review

209 Scopus citations


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 languageEnglish (US)
Pages (from-to)781-795
Number of pages15
JournalCell stem cell
Issue number6
StatePublished - Jun 5 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology


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