RRC ID 80756
Author Tsioras K, Smith KC, Edassery SL, Garjani M, Li Y, Williams C, McKenna ED, Guo W, Wilen AP, Hark TJ, Marklund SL, Ostrow LW, Gilthorpe JD, Ichida JK, Kalb RG, Savas JN, Kiskinis E.
Title Analysis of proteome-wide degradation dynamics in ALS SOD1 iPSC-derived patient neurons reveals disrupted VCP homeostasis.
Journal Cell Rep
Abstract Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS) through gain-of-function effects, yet the mechanisms by which misfolded mutant SOD1 (mutSOD1) protein impairs human motor neurons (MNs) remain unclear. Here, we use induced-pluripotent-stem-cell-derived MNs coupled to metabolic stable isotope labeling and mass spectrometry to investigate proteome-wide degradation dynamics. We find several proteins, including the ALS-causal valosin-containing protein (VCP), which predominantly acts in proteasome degradation and autophagy, that degrade slower in mutSOD1 relative to isogenic control MNs. The interactome of VCP is altered in mutSOD1 MNs in vitro, while VCP selectively accumulates in the affected motor cortex of ALS-SOD1 patients. Overexpression of VCP rescues mutSOD1 toxicity in MNs in vitro and in a C. elegans model in vivo, in part due to its ability to modulate the degradation of insoluble mutSOD1. Our results demonstrate that VCP contributes to mutSOD1-dependent degeneration, link two distinct ALS-causal genes, and highlight selective protein degradation impairment in ALS pathophysiology.
Volume 42(10)
Pages 113160
Published 2023-10-31
DOI 10.1016/j.celrep.2023.113160
PII S2211-1247(23)01172-5
PMID 37776851
PMC PMC10785776
MeSH Amyotrophic Lateral Sclerosis* / genetics Amyotrophic Lateral Sclerosis* / metabolism Animals Caenorhabditis elegans / metabolism Homeostasis Humans Induced Pluripotent Stem Cells* / metabolism Motor Neurons / metabolism Mutation Proteome / metabolism Superoxide Dismutase-1 / genetics Superoxide Dismutase-1 / metabolism Valosin Containing Protein / metabolism
C.elegans tm544