Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis.

Journal Article (Journal Article)

Although mutations in several genes with diverse functions have been known to cause amyotrophic lateral sclerosis (ALS), it is unknown to what extent causal mutations impinge on common pathways that drive motor neuron (MN)-specific neurodegeneration. In this study, we combined induced pluripotent stem cells-based disease modeling with genome engineering and deep RNA sequencing to identify pathways dysregulated by mutant SOD1 in human MNs. Gene expression profiling and pathway analysis followed by pharmacological screening identified activated ERK and JNK signaling as key drivers of neurodegeneration in mutant SOD1 MNs. The AP1 complex member JUN, an ERK/JNK downstream target, was observed to be highly expressed in MNs compared with non-MNs, providing a mechanistic insight into the specific degeneration of MNs. Importantly, investigations of mutant FUS MNs identified activated p38 and ERK, indicating that network perturbations induced by ALS-causing mutations converge partly on a few specific pathways that are drug responsive and provide immense therapeutic potential.

Full Text

Duke Authors

Cited Authors

  • Bhinge, A; Namboori, SC; Zhang, X; VanDongen, AMJ; Stanton, LW

Published Date

  • April 11, 2017

Published In

Volume / Issue

  • 8 / 4

Start / End Page

  • 856 - 869

PubMed ID

  • 28366453

Pubmed Central ID

  • PMC5390134

Electronic International Standard Serial Number (EISSN)

  • 2213-6711

Digital Object Identifier (DOI)

  • 10.1016/j.stemcr.2017.02.019


  • eng

Conference Location

  • United States