The folding state of polypeptides is easily perturbed by adverse conditions. Failure to properly fold polypeptides into the appropriate three-dimensional structure impacts directly on the ability to synthesize useful proteins and introduces a measure of inefficiency into the cells economy. But protein malfolding has an additional consequence that is unrelated to the lack of properly folded polypeptides but is rather mediated by the presence of malfolded ones. Numerous genetic and biochemical observations suggest that structures elaborated by polypeptides that fail to attain their proper three dimensional fold may exert a deleterious effect on cellular function. This process, also referred to as "proteotoxicity", appears to be particularly important to the fate of non-renewable cells of long-lived organisms in which accumulating malfolded proteins can exert their deleterious effects over extended periods of time. The hypothesized contribution of such "proteotoxins" to cellular aging fits our intuitive notions of aging as a time and use-dependent process. The progressive aging of the human population has led to an increase in the incidence of diseases hypothesized to be associated with various forms of proteotoxicity. These include not only the classic examples of the Amyloidoses, Prion disorders, Alzheimer''''''''s disease and various forms of Parkinsonism - in all of which the accumulation of abnormal proteins can be readily observed - but also, we hypothesize, others such as type-II diabetes mellitus in which low-levels protein malfolding in the secretory pathway, over time, might contribute to exhaustion of the insulin-producing islet beta cell.

The long-term goal of our research is to identify new components of the cellular response to proteotoxic stress and to integrate these into an understanding of pathophysiology of common human diseases. We expect that our basic research program into the biochemistry, cell biology and genetics of the cellular response to proteotoxins will contribute to the scaffold upon which translational research can later build to create pharmacological tools to manipulate the responses to favorable ends.