Activation of autophagy attenuates motor deficits and extends lifespan in a C. elegans model of ALS

Hui Xu, Congcong Jia, Cheng Cheng, Haifeng Wu, Huaibin Cai, Weidong Le

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in Cu/Zn–superoxide dismutase 1 (SOD1) are linked to amyotrophic lateral sclerosis (ALS). Using a line of ALS-related mutant human SOD1 (hSOD1) transgenic Caenorhabditis elegans, we determined the effects of metformin on the progression of ALS-like pathological abnormalities. We found that metformin significantly extended the lifespan, improved motor performance, and enhanced antioxidant activity of mutant worms. We further showed that metformin enhanced expression of lgg-1, daf-16, skn-1 and other genes known to regulate autophagy, longevity and oxidative stress in hSOD1 transgenic worms. Accordingly, overexpression of lgg-1 or daf-16 attenuated the aging and pathological abnormalities of mutant human SOD1 worms, while genetic deletion of lgg-1 or daf-16 abolished the beneficial effects of metformin. Collectively, we demonstrate that metformin protects against mutant SOD1-induced cytotoxicity in part through enhancement of autophagy and extends lifespan through daf-16 pathway. Our findings suggest that metformin could be further explored as a potential therapeutic agent in treating ALS.

Original languageEnglish (US)
Pages (from-to)52-61
Number of pages10
JournalFree Radical Biology and Medicine
Volume181
DOIs
StatePublished - Mar 2022

Keywords

  • ALS
  • Autophagy
  • Lifespan
  • Metformin
  • Neuroprotection

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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