Protein folding plays an important role in a number of neurodegenerative conditions, such as parkinson's, alzheimer's and motor neuron diseases. Accumulating evidence suggests that environmental agents may contribute to the pathology of these common disorders by perturbing protein folding, either directly or indirectly through their effects on cell metabolism. However, little is known how cells adapt to the threat of environmentally-induced proteotoxicity. This study will exploit arsenic as a model for an environmental toxin that adversely affects protein folding and one with important public health hazard affecting multiple organ systems. We recently identified AIRAP as an adaptor of proteasomes, the cell's major protein degradation apparatus. Cellular conditions that impair proteasomal activity such as exposure to arsenite induce expression of AIRAP. Our genetic and biochemical data indicate a protective role for the AIRAP proteasome complex, under protein misfolding conditions. The initial characterization of a second protein, AIRAPL (Q8WV99; a highly homologous protein to AIRAP), has shown AIRAPL to be an additional proteasome adaptor with distinct cellular functions under basal and protein misfolding conditions. RNAi experiments in C. elegans, revealed a protective role for AIRAPL in ageing, a protein misfolding related process. In an effort to understand the cellular functions of AIRAPL, identification of proteins whose degradation depends on AIRAPL will be identified by a proteomic approaches. The emphasis will be to examine the toxic effect of the identified proteins in the biochemical approach and relate them to the ageing process. The goal of this research program is to reduce the cellular adaptations to protein malfolding induced by environmental toxins, to their molecular constituents. This will lay the groundwork for identifying relevant biomarkers of exposure and for future preventive and therapeutic interventions against protein misfolding diseases.
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