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We are interested in the protein pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD). Our window to these related neurodegenerative diseases is protein structural biology. AD and PD are both characterized by the deposition of fibrillar aggregates (amyloid in AD, the Lewy body in PD) comprising normal neuronal proteins. There is strong circumstantial evidence in each case that aggregation initiates a cascade of events that culminates in neurodegeneration. Because the inhibition of aggregation is a plausible therapeutic strategy, it is critical to elucidate the molecular details of aggregate structure as well as the mechanism by which aggregates are formed. Our approach is a reductionist one: purified proteins from recombinant or synthetic sources are studied in vitro under controlled conditions selected to analyze particular factors that may be important in vivo. In an effort to follow in vivo aggregation directly, we have initiated collaborative studies aimed at the development of imaging agents that could be used to flow aggregation by noninvasive imaging (SPECT). The structure of the disease-specific fibrillar protein aggregates is analyzed by several developing methods: solid-state NMR, Fourier-transform infrared spectroscopy, and atomic force microscopy. This work involves collaborations between our group and groups that are expert in the relevant technology.

In both AD and PD, the aggregating protein is a normal neuronal protein (Aß in AD, the a-synuclein in PD) of undetermined function. The possibility exists that disease results from a loss of the normal protein rather than by the accumulation of aggregates. Studies are in progress to determine the normal role of these proteins. These studies involve molecular biological, biochemical, and cell biological approaches to the elucidation of protein-protein interactions. Many of our hypotheses will be tested in drosophila and mouse models using small molecules identified by screening.

Last updated February 09, 2005