Pre-clinical Model for Pharmacological Upregulation of Molecular Chaperones

Lewy bodies including alpha-synuclein in substantia nigra neurons are characteristic of Parkinson's disease. These aggregates may cause the disease or may represent disease-causing protein folding problems. Cells respond to physical and chemical stresses by increasing levels of heat shock or stress proteins (Hsps). This increase in Hsp expression is mediated by heat shock transcription factor 1 (HSF1). Hsps are chaperones that enhance protein folding/refolding. This proposal is to prepare an in vitro model and a transgenic pre-clinical model for the pharmacological upregulation of HSF1 activity. In initial experiments, the in vitro model will be used to test the hypothesis that increased expression of the cohort of Hsps will protect against toxicity from alpha-synuclein or MPTP, a chemical that causes a Parkinson-like disease in animals. The animal model will serve to determine whether a therapy based on elevation of HSF1 activity is feasible in principle, i.e., whether chronically elevated levels of Hsps are tolerated by a mammalian animal.