Identification of neuroprotective genes against alpha-synuclein toxicity using a Caenorhabditis elegans Parkinson disease model

Recent functional analyses of nine gene products linked to familial forms of Parkinson disease (PD) have revealed several cellular mechanisms that are associated with PD pathogenesis. For example, alpha-synuclein (alpha-syn), a primary component of Lewy bodies found in both familial and idiopathic forms of PD, has been shown to cause defects in proteasomal and lysosomal protein degradation machineries and induce mitochondrial/oxidative stress. These findings are further supported by the fact that additional gene products are involved in the same pathways. While these studies have been invaluable to elucidate the etiology of this disease, it has been reported that monogenic forms of PD only account for 5-10% of all PD cases, indicating that multiple genetic susceptibility factors and intrinsic metabolic changes associated with aging may play a significant role. Here we report the use of an organism, Caenorhabditis elegans, to model two central PD pathological features to rapidly identify genetic components that modify alpha-syn misfolding in body wall muscles and neurodegeneration in DA neurons. We determined that proteins that function in lysosomal protein degradation, signal transduction, vesicle trafficking, and glycolysis, when knocked down by RNAi, enhanced alpha-syn misfolding. Furthermore, these components, when overexpressed, rescued DA neurons from alpha-syn-induced neurodegeneration, and several of them have been validated using mammalian system. Taken together, this study represents a novel set of gene products that are putative genetic susceptibility loci and potential therapeutic targets for PD. (Published By University of Alabama Libraries