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 language | English (US) |
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Pages (from-to) | 644-650 |
Number of pages | 7 |
Journal | Acta Pharmacologica Sinica |
Volume | 34 |
Issue number | 5 |
DOIs | |
State | Published - May 2013 |
Keywords
- amyotrophic lateral sclerosis
- autophagy
- axon guidance
- C. elegans
- daf-2(e1370)
- motor defect
- SOD1
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)