RRC ID 81078
Author Au WH, Miller-Fleming L, Sanchez-Martinez A, Lee JA, Twyning MJ, Prag HA, Raik L, Allen SP, Shaw PJ, Ferraiuolo L, Mortiboys H, Whitworth AJ.
Title Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes in C9orf72 ALS/FTD models.
Journal Life Sci Alliance
Abstract Mitochondrial dysfunction is a common feature of C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this is a cause or consequence of the pathogenic process. Analysing multiple aspects of mitochondrial biology across several Drosophila models of C9orf72-ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss of locomotor performance. Notably, only genetic manipulations that reversed the oxidative stress levels were also able to rescue C9orf72 locomotor deficits, supporting a causative link between mitochondrial dysfunction, oxidative stress, and behavioural phenotypes. Targeting the key antioxidant Keap1/Nrf2 pathway, we found that genetic reduction of Keap1 or pharmacological inhibition by dimethyl fumarate significantly rescued the C9orf72-related oxidative stress and motor deficits. Finally, mitochondrial ROS levels were also elevated in C9orf72 patient-derived iNeurons and were effectively suppressed by dimethyl fumarate treatment. These results indicate that mitochondrial oxidative stress is an important mechanistic contributor to C9orf72 pathogenesis, affecting multiple aspects of mitochondrial function and turnover. Targeting the Keap1/Nrf2 signalling pathway to combat oxidative stress represents a therapeutic strategy for C9orf72-related ALS/FTD.
Volume 7(9)
Published 2024-9-1
DOI 10.26508/lsa.202402853
PII 7/9/e202402853
PMID 38906677
PMC PMC11192839
MeSH Amyotrophic Lateral Sclerosis* / genetics Amyotrophic Lateral Sclerosis* / metabolism Animals C9orf72 Protein* / genetics C9orf72 Protein* / metabolism Dimethyl Fumarate / pharmacology Disease Models, Animal* Drosophila Proteins / genetics Drosophila Proteins / metabolism Frontotemporal Dementia* / genetics Frontotemporal Dementia* / metabolism Humans Kelch-Like ECH-Associated Protein 1* / genetics Kelch-Like ECH-Associated Protein 1* / metabolism Male Mitochondria* / metabolism Mitophagy / genetics NF-E2-Related Factor 2* / genetics NF-E2-Related Factor 2* / metabolism Oxidative Stress* Phenotype* Reactive Oxygen Species / metabolism Signal Transduction*
Resource
Drosophila 3016R-2