Establishing a novel C. elegans model to investigate the role of autophagy in amyotrophic lateral sclerosis

Jia Li, Kai Xing Huang, Wei Dong Le

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Aim:To develop a C. elegans model of amyotrophic lateral sclerosis (ALS) and to evaluate the role of autophagy in the disease.Methods:Stable transgenic worms expressing the G93A mutant form of Cu,Zn-superoxide dismutase (SOD1) in GABAergic motor neurons were generated. Axon guidance and protein aggregation in the motor neurons were observed with fluorescence microscopy. A paralysis assay was performed to evaluate the motor function of the transgenic worms. The expression of autophagic genes in daf-2(e1370) mutants was analyzed using real-time PCR. The reporter GFP::LGG-1 was used to verify whether autophagy was induced in motor neurons.Results:Expression of G93A SOD1 in motor neurons caused age-dependent motor defects accompanied by significant SOD1 aggregation and axon guidance failure. After 12 d, over 80% of the G93A worms became paralyzed, whereas less than 10% of the controls showed a paralytic phenotype. In the daf-2(e1370) mutants of C. elegans, the levels of autophagic genes bec-1, atg-7, lgg-1, and atg-18 were upregulated by approximately 1.5-fold, the level of unc-51 increased by approximately fourfold, and autophagosomes in motor neurons was markedly increased. Crossing the daf-2(e1370) mutation into the G93A SOD1 mutant worms significantly ameliorated the motor defects, SOD1 aggregation, and axon guidance failure.Conclusion:G93A SOD1 expression in motor neurons of C. elegans results in characteristic alterations of ALS. Increased autophagy protects C. elegans motor neurons against the toxicity of mutant SOD1.

Original languageEnglish (US)
Pages (from-to)644-650
Number of pages7
JournalActa Pharmacologica Sinica
Volume34
Issue number5
DOIs
StatePublished - May 2013

Keywords

  • amyotrophic lateral sclerosis
  • autophagy
  • axon guidance
  • C. elegans
  • daf-2(e1370)
  • motor defect
  • SOD1

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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