title: Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis.
abstract: 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.
authors.affiliation: Stem Cell and Regenerative Biology, Genome Institute of Singapore, Singapore 138672, Singapore. Electronic address: a.bhinge@exeter.ac.uk.
authors.forename: Akshay
authors.initials: A
authors.lastname: Bhinge
authors.affiliation: Stem Cell and Regenerative Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Seema C
authors.initials: SC
authors.lastname: Namboori
authors.affiliation: Program for Neuroscience and Behavioral Disorders, Duke-NUS Medical School, Singapore 169857, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Program for Neuroscience and Behavioral Disorders, Duke-NUS Medical School, Singapore 169857, Singapore.
authors.forename: Antonius M J
authors.initials: AMJ
authors.lastname: VanDongen
authors.affiliation: Stem Cell and Regenerative Biology, Genome Institute of Singapore, Singapore 138672, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore. Electronic address: stantonl@gis.a-star.edu.sg.
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Stanton
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D005818:Genetic Engineering; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D017354:Point Mutation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D000072105:Superoxide Dismutase-1 / Q000235:genetics* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D000072105:Superoxide Dismutase-1
keywords: ALS; CRISPR-Cas9; ERK; FUS; JNK; JUN; SOD1; TP53; WNT; p38