Investigation of the pathogenic mechanisms of neurodegenerative diseases
Recent breakthrough in genetic studies of Parkinson's disease has provided the first clue that mutations in α-synuclein (a synaptic vesicle-associated protein), parkin (an ubiquitin-protein ligase), UCH-L1 (a deubiquitinating enzyme), and DJ-1 (an ubiquitously expressed protein of unknown function) may be involved in the pathogenesis of Parkinson's disease. We are using an interdisciplinary approach to delineate the molecular pathways by which the mutations in these proteins lead to neurodegeneration and to identify other molecular players in the pathogenic pathways. For example, our recent work provides first evidence that DJ-1 may function as a cysteine protease and this function is completely abolished by familial Parkinson's disease-associated L166P mutation. Our proteomic analyses reveal that UCH-L1 is a major target of oxidative damage in idiopathic Parkinson's and Alzheimer's disease brains, raising the possibility that pathogenic effects similar to those caused by UCH-L1 genetic mutations might be achieved by the identified oxidative modifications of UCH-L1 in sporadic forms of the diseases. In addition, we are very interested in understanding the role of abnormal vesicular trafficking in neurodegenerative diseases. We recently found that HAP1, a novel protein that is associated with the Huntington's disease protein huntingtin, functions in endosomal trafficking, suggesting that abnormal vesicular trafficking may contribute to the pathogenic mechanism of Huntington's disease. Through our studies, we hope to define new protein targets for understanding and treating neurodegenerative disorders, such as Parkinson's, Alzheimer's, and Huntington's diseases.
2. Elucidation of the molecular basis of neurotransmitter release and its regulation
Another major goal of our research is to elucidate the molecular mechanisms underlying neurotransmitter release in both normal and pathological states. As a first step towards this goal, we have identified two novel neuronal proteins, called SNIP and Spring, that interact with SNAP-25, an essential component of the neurotransmitter release machinery. Our preliminary studies suggest that these novel proteins may function in the spatial organization and/or temporal coordination of the exocytotic and endocytotic components. We are characterizing these new proteins complexes at the nerve terminals, and determining the functional importance of these novel proteins and their protein-protein interactions using a combination of biochemical, cell biological, and molecular genetic approaches, including targeted gene disruption.