Increased lifespan in transgenic Caenorhabditis elegans overexpressing human alpha-synuclein.
alpha-Synuclein is a short 14-kDa protein found in pathological lesions of age-related neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and multiple system atrophy. Its overexpression in transgenic mice, rats, Drosophila melanogaster, and Caenorhabditis elegans recapitulates many of the pathologic features observed in human Parkinson's disease including loss of dopaminergic neurons and motor deficits. Integrated transgenic C. elegans lines were generated that overexpress either human wildtype (WT) or mutant (A53T) forms. These transgenic lines demonstrated approximately 25% increase in lifespan (p<0.0001) compared to controls. When the transgenes were crossed into long-lived daf-2 (m577) or daf-2 (e1370) genetic backgrounds, the lifespan increase was also approximately 25% in comparison to the corresponding daf-2 strains (p<0.05). Pharyngeal pumping and egg laying were significantly decreased in the overexpressing transgenic lines, and lifespan increases were attenuated when lines were grown on thick bacterial lawns, suggesting that caloric restriction may explain some of the effects on lifespan. These studies provide initial evidence for a beneficial role of human alpha-synuclein in influencing lifespan.