Establishing a novel C. elegans model to investigate the role of autophagy in amyotrophic lateral sclerosis.
Acta Pharmacol Sin
; 34(5): 644-50, 2013 May.
Article
em En
| MEDLINE
| ID: mdl-23503474
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 GFPLGG-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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Autofagia
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Caenorhabditis elegans
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Modelos Animais de Doenças
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Esclerose Lateral Amiotrófica
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article