Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis
| Autor: | Lawrence W. Stanton, Akshay Bhinge, Xiaoyu Zhang, Antonius M.J. VanDongen, Seema C. Namboori |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway MAP Kinase Signaling System Proto-Oncogene Proteins c-jun Induced Pluripotent Stem Cells Mutant SOD1 p38 Biology Biochemistry Article WNT 03 medical and health sciences Superoxide Dismutase-1 Genetics medicine Humans Point Mutation TP53 Induced pluripotent stem cell lcsh:QH301-705.5 JUN Cells Cultured FUS Motor Neurons lcsh:R5-920 Amyotrophic Lateral Sclerosis Neurodegeneration Wnt signaling pathway Cell Biology medicine.disease Molecular biology Cell biology Transcription Factor AP-1 Gene expression profiling ERK AP-1 transcription factor 030104 developmental biology lcsh:Biology (General) JNK ALS CRISPR-Cas9 lcsh:Medicine (General) Genetic Engineering Developmental Biology |
| Zdroj: | Stem Cell Reports Stem Cell Reports, Vol 8, Iss 4, Pp 856-869 (2017) |
| ISSN: | 2213-6711 |
| DOI: | 10.1016/j.stemcr.2017.02.019 |
| Popis: | Summary 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. Highlights • Genome correction of SOD1 E100G mutation corrects ALS phenotypes in MNs • Activation of MAPK, AP1, WNT, cell-cycle, and p53 signaling in ALS MNs • Pharmacological screening uncovers ERK and JNK signaling as therapeutic targets • Susceptibility of MNs to degeneration may be due to heightened JUN activity in MNs In this article, Bhinge, Stanton, and colleagues use genome editing of patient-derived iPSCs to model ALS phenotypic defects in vitro. Transcriptomic analysis of disease MNs reveals activation of MAPK, AP1, WNT, cell-cycle, and p53 signaling in ALS MNs. Pharmacological screening uncovers activated ERK and JNK signaling as therapeutic targets in ALS. |
| Databáze: | OpenAIRE |
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