Environmental or occupational exposure to manganese (Mn) causes a neuropathy resembling idiopathic Parkinson's disease (PD), characterized by motor deficits and damage to dopaminergic (DAergic) nuclei of the the basal ganglia. Mitochondria! dysfunction, oxidative damage, and protein aggregation have been implicated in the pathobiology of PD. The complexity of the vertebrate brain has hindered understanding of molecular mechanisms associated with this disorder. The nematode, Caenorhabditis elegans (C. elegans) and mammals share a highly conserved genetic code with all genes responsible for DA biosynthesis, packaging, and reuptake present and functional in the worm. Exposure of C. elegans to Mn results in DAergic neurodegeneration, consistent with observations in mammals. Thus, the C. elegans offers an 1 innovative and powerful platform to evaluate the molecular and functional mechanisms associated with Mn- induced DAergic neurodegeneration and a unique model for evaluating gene-environment interactions. Our overall hypothesis is that knockdown and loss-of-function mutations of the PD-associated genes, dj-1,and pinkl, and their related chaperone proteins confer selective vulnerability to DAergic neurons rendering them susceptible to an accelerated neurodegeneration upon exposure to Mn. We will test the following Specific Aims: (1A) Knockdown and loss-of-function mutations in dj-1and pinkl render C. elegans susceptible to oxidant-induced DAergic neurodegeneration which is amplified by Mn exposure, (1B)Overexpression of DJ- 1 and PINK1 protects C. elegans against oxidant-induced DAergic neurodegeneration mediated by 6-OHDA and Mn, (2) Knockdown of heat shock protein 70 (hsp70) and carboxyl terminus of Hsc70-interacting protein (CHIP) orthologues inhibits DJ-1 and PINK1 translocation to the mitochondria rendering C. elegans more susceptible to 6-OHDA and Mn-induced DAergic neurodegeneration. Using RNAi, site-directed mutagenesis and overexpression of PD-associated genes to generate the worm phenotypes, we will assess DAergic neurodegeneration by GFP fluorescence and a-synuclein aggregation assays. Oxidative injury will be assayed by measuring F2- and F3-isoprostanes, ATP and mitochondrial membrane potential. Understanding the relationship between genetic vulnerability and Mn exposure will provide critical insights into the mechanisms of Mn-induced toxicity and the development of novel therapeutic neuroprotective strategies.
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