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

Publication ,  Journal Article
Bhinge, A; Namboori, SC; Zhang, X; VanDongen, AMJ; Stanton, LW
Published in: Stem Cell Reports
April 11, 2017

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.

Duke Scholars

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Published In

Stem Cell Reports

DOI

EISSN

2213-6711

Publication Date

April 11, 2017

Volume

8

Issue

4

Start / End Page

856 / 869

Location

United States

Related Subject Headings

  • Transcription Factor AP-1
  • Superoxide Dismutase-1
  • Proto-Oncogene Proteins c-jun
  • Point Mutation
  • Motor Neurons
  • MAP Kinase Signaling System
  • Induced Pluripotent Stem Cells
  • Humans
  • Genetic Engineering
  • Cells, Cultured
 

Citation

APA
Chicago
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MLA
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Bhinge, A., Namboori, S. C., Zhang, X., VanDongen, A. M. J., & Stanton, L. W. (2017). Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis. Stem Cell Reports, 8(4), 856–869. https://doi.org/10.1016/j.stemcr.2017.02.019
Bhinge, Akshay, Seema C. Namboori, Xiaoyu Zhang, Antonius M. J. VanDongen, and Lawrence W. Stanton. “Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis.Stem Cell Reports 8, no. 4 (April 11, 2017): 856–69. https://doi.org/10.1016/j.stemcr.2017.02.019.
Bhinge A, Namboori SC, Zhang X, VanDongen AMJ, Stanton LW. Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis. Stem Cell Reports. 2017 Apr 11;8(4):856–69.
Bhinge, Akshay, et al. “Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis.Stem Cell Reports, vol. 8, no. 4, Apr. 2017, pp. 856–69. Pubmed, doi:10.1016/j.stemcr.2017.02.019.
Bhinge A, Namboori SC, Zhang X, VanDongen AMJ, Stanton LW. Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis. Stem Cell Reports. 2017 Apr 11;8(4):856–869.
Journal cover image

Published In

Stem Cell Reports

DOI

EISSN

2213-6711

Publication Date

April 11, 2017

Volume

8

Issue

4

Start / End Page

856 / 869

Location

United States

Related Subject Headings

  • Transcription Factor AP-1
  • Superoxide Dismutase-1
  • Proto-Oncogene Proteins c-jun
  • Point Mutation
  • Motor Neurons
  • MAP Kinase Signaling System
  • Induced Pluripotent Stem Cells
  • Humans
  • Genetic Engineering
  • Cells, Cultured