Parkinson's disease (PD) results from an imbalance in cellular mechanisms designed to cope with environmental stresses to neurons. The two major clinical hallmarks of PD, protein inclusions termed Lewy bodies and dopamine neuron degeneration, are representative of failure in the intracellular management of stress. While genetic forms of PD are rare, these mutations highlight the involvement of pathways that regulate protein folding and oxidative damage in cells. Given the predominance of sporadic PD, environmental sources of toxins may serve as potential risk factors for individuals with specific genetic predispositions. One environmental factor that may contribute to PD is exposure to certain bacteria that produce proteasome inhibitors, such as specific strains of the order Actinomycetales. Here we propose to utilize the nematode roundworm, C. elegans, to mechanistically investigate exposure to bacterial strains implicated in PD. Our lab has previously established this worm model for rapid evaluation of factors influencing both the misfolding of human alpha-synuclein and neuroprotection of dopamine neurons.
The aims of our proposal include investigating dopamine neuron degeneration as caused by bacterial exposure in wild-type worms and in genetically defined backgrounds. We will evaluate susceptibility to bacterial exposure in animals defective in worm homologs of known PD genes, in addition to novel PD gene targets obtained from a large-scale RNA interference (RNAi) screen we have performed. Transgenic nematodes containing fluorescent reporter gene constructs will be used to distinguish systemic effects of exposure on various neuronal subtypes, general stress response, and proteasomal inhibition. Differential changes in gene expression in response to bacterial exposure will also be profiled using whole-genome oligonucleotide microarrays to identify potential genes regulated in response to environmental toxins. Relevance to Public Health: The interplay between genetic predisposition and susceptibility to environmental insults lies at the core of PD. Risk factors are best evaluated using systems wherein environmental conditions and genetic differences are strictly controlled. C. elegans, a microscopic worm with precisely 8 dopamine neurons, shares about half of its genes with humans and represents an ideal system to rapidly examine potential sources environmental toxins that may influence development of PD. ? ?
| Kritzer, Joshua A; Hamamichi, Shusei; McCaffery, J Michael et al. (2009) Rapid selection of cyclic peptides that reduce alpha-synuclein toxicity in yeast and animal models. Nat Chem Biol 5:655-63 |
| Caldwell, Kim A; Tucci, Michelle L; Armagost, Jafa et al. (2009) Investigating bacterial sources of toxicity as an environmental contributor to dopaminergic neurodegeneration. PLoS One 4:e7227 |
