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

  
@article{APS5763,
	author = {Jia Li and Kai-xing Huang and Wei-dong Le},
	title = {Establishing a novel C. elegans model to investigate the role of autophagy in amyotrophic lateral sclerosis},
	journal = {Acta Pharmacologica Sinica},
	volume = {34},
	number = {5},
	year = {2016},
	keywords = {},
	abstract = {Jia LI, Kai-xing Huang, Wei-dong LE*
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China
 
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.

 
Keywords: amyotrophic lateral sclerosis; C. elegans; SOD1; motor defect; axon guidance; autophagy; daf-2(e1370)
 
This work was supported by grants from the National Natural Sciences Foundation of China (No 81171201 and No 39070925) and the National Basic Research Program of China (No 2011CB510003).
* To whom correspondence should be addressed. 
E-mail wdle@sibs.ac.cn
Received 2012-11-07    Accepted 2012-12-20},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/5763}
}