Amyloid deposits are commonly found in neurodegenerative diseases. Alzheimer disease (AD) is characterized by several kinds of deposits: extracellular beta-amyloid containing plaques and intraneuronal tau-containing tangles and, quite often, alpha-synuclein-containing Lewy bodies. This proposal aims to determine the structure of amyloid fibrils formed by, alpha-synuclein through biochemical and biophysical methods. In particular, we will exploit recent advances in site-directed spin labeling and EPR spectroscopy to determine alpha-synuclein fibril structure. We will also use nitroxide-scanning experiments to determine the local secondary structure. This information in combination with mapping of inter- and intra-molecular distances should allow us to build 3-dimensional models of alpha-synuclein fibrils. Similar strategies will be used to determine the molecular mechanism of alpha-synuclein membrane interaction. Membrane interactions are implicated in the physiologic function of alpha-synuclein in presynaptic terminals of neurons, whereas mutations linked to neurodegeneration are known to modulate the membrane interactions of alpha-synuclein and to enhance the formation of amyloid fibrils.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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University of Southern California
Los Angeles
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