RRC ID 80816
Author Wong CH, Rahat A, Chang HC.
Title Fused in sarcoma regulates glutamate signaling and oxidative stress response.
Journal Free Radic Biol Med
Abstract Mutations in fused in sarcoma (fust-1) are linked to ALS. However, how these ALS causative mutations alter physiological processes and lead to the onset of ALS remains largely unknown. By obtaining humanized fust-1 ALS mutations via CRISPR-CAS9, we generated a C. elegans ALS model. Homozygous fust-1 ALS mutant and fust-1 deletion animals are viable in C. elegans. This allows us to better characterize the molecular mechanisms of fust-1-dependent responses. We found FUST-1 plays a role in regulating superoxide dismutase, glutamate signaling, and oxidative stress. FUST-1 suppresses SOD-1 and VGLUT/EAT-4 in the nervous system. FUST-1 also regulates synaptic AMPA-type glutamate receptor GLR-1. We found that fust-1 ALS mutations act as loss-of-function in SOD-1 and VGLUT/EAT-4 phenotypes, whereas the fust-1 ALS mutations act as gain-of-function in redox homeostasis and the microbe-induced oxidative stress response. We hypothesized that FUST-1 is a link between glutamate signaling and SOD-1. Our results may provide new insights into the human ALS alleles and their roles in pathological mechanisms that lead to ALS.
Volume 210
Pages 172-182
Published 2024-1-1
DOI 10.1016/j.freeradbiomed.2023.11.015
PII S0891-5849(23)01116-4
PMID 38007141
PMC PMC10872661
MeSH Amyotrophic Lateral Sclerosis* / genetics Amyotrophic Lateral Sclerosis* / pathology Animals Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Disease Models, Animal Glutamates / metabolism Humans Mutation Oxidation-Reduction Oxidative Stress / genetics RNA-Binding Protein FUS* / genetics RNA-Binding Protein FUS* / metabolism Superoxide Dismutase / genetics Superoxide Dismutase / metabolism Superoxide Dismutase-1 / genetics
Resource
C.elegans tm4439 tm776