The cause of many age-related neurodegenerative disorders, including Parkinson's disease, ALS, and several polyglutamine expansion diseases, is accumulation in neurons of various mutant or damaged polypeptides. These toxic abnormal proteins can aggregate in cells and form large inclusion bodies, and there is an ongoing discussion in the field how aggregation of these proteins influences neurotoxicity. Recently it became clear that in contrast to protein aggregation in a test tube, aggregation of damaged or mutant polypeptides in vivo is a complicated tightly regulated process that involves many cellular factors. This proposal is designed to identify cellular components that promote aggregation of abnormal proteins. The proposal is based on a yeast model of human polyglutamine (polyQ) expansion diseases. This model allowed us to demonstrate that there are two distinct steps in polyQ aggregation - (1) seeding and (2) growth of aggregates. These steps require two distinct sets of cellular components, including a prion-like protein Rnql in a prion conformation. This model will be used for screens for cellular mutations that affect various steps of polyQ aggregation. Mutants with defects in polyQ aggregation will be tested for their ability to carry out various steps of the aggregation process. Then, it will be established which of the newly identified cellular factors that promote polyQ aggregation are also involved in aggregation of mutant proteins important for development of other agerelated diseases, including synphilin 1, ataxin 1 and PABP2. This work will lay the basis for further study of mechanisms of protein aggregation in neurons and aged mammalian cells.
