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

• Published in: Stem cell reports Vol. 8; no. 4; pp. 856 - 869
• Main Authors: Bhinge, Akshay, Namboori, Seema C., Zhang, Xiaoyu, VanDongen, Antonius M.J., Stanton, Lawrence W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.04.2017; Elsevier
• Subjects: ALS; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Cells, Cultured; CRISPR-Cas9; ERK; FUS; Genetic Engineering; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - pathology; JNK; JUN; MAP Kinase Signaling System; Motor Neurons - metabolism; Motor Neurons - pathology; p38; Point Mutation; Proto-Oncogene Proteins c-jun - metabolism; SOD1; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism; TP53; Transcription Factor AP-1 - metabolism; WNT; JUN; p38; FUS; CRISPR-Cas9; JNK; ALS; WNT; TP53; SOD1; ERK
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2017.02.019

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. •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.