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PMID:37776851

Analysis of proteome-wide degradation dynamics in ALS SOD1 iPSC-derived patient neurons reveals disrupted VCP homeostasis.

Cell reports | 2023

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.

Pubmed ID: 37776851

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Associated grants

Agency: NIA NIH HHS, United States
Id: R01 AG078796
Agency: NINDS NIH HHS, United States
Id: R01 NS134166
Agency: NINDS NIH HHS, United States
Id: R21 NS107761
Agency: NINDS NIH HHS, United States
Id: R01 NS097850
Agency: NINDS NIH HHS, United States
Id: R01 NS124802
Agency: NINDS NIH HHS, United States
Id: R01 NS104219
Agency: NINDS NIH HHS, United States
Id: R01 NS122908
Agency: NINDS NIH HHS, United States
Id: R01 NS096746

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