A recent discovery by our laboratory and others has revealed a new gene that is linked to several families with hereditary Parkinson Disease. This gene codes for the PTEN Induced Kinase-1 (or PINK1) protein which when mutated results in an early onset of the disease (less than 50 years of age). PINK1 is a putative protein kinase that is highly conserved in evolution and analysis of its amino acid sequence suggests that it may be a member of a small family of novel proteins. Kinases are enzymes which can modify other target proteins by the addition of phosphate groups. This results in changes in structure and function of the proteins that is often used as a means of regulating metabolic pathways. Our preliminary biochemical and cellular studies have revealed that PINK1 distributes to mitochondrial as well as microsomal fractions and co-localizes with another Parkinson's disease protein, parkin. Mitochondrial are responsible for energy generation within cells and are highly susceptible to external stress and toxic insults. It has been proposed that PINK1 may act by protecting mitochondrial and that when mutated this normal function is lost. This would then compromise the viability of nerve cells and lead to disruption of normal metabolism and possible cell death. We propose to advance our understanding of PINK1 and its relationship to Parkinson's disease by determining the kinase's structure using high resolution nuclear magnetic resonance (NMR) and x-ray diffraction of single protein crystals. This will provide information on the molecular organization of PINK1 and indicate how it functions as well as specific domains that are involved in kinase activity. These investigations will be complemented by a search for new PINK1 binding partners to determine which pathways it is capable of regulating and how these fit into the overall cellular events that lead to Parkinson's disease. We feel that by understanding PINK1 structure and function, we may reveal new insights into the pathogenic signaling pathways in Parkinson's disease and identify effective therapeutics to regulate these processes.