University of California Irvine, (UCI)

Interaction of Amyloid Aß and a-Synuclein with Membranes - Implications for their Pathogenesis in Alzheimer's and Parkinson's Diseases

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It is increasingly clear that many of the neurodegenerative diseases associated with aging share a number of common features. Alzheimer’s and Parkinson’s diseases are the most common and debilitating forms of age-related neurodegenerative diseases.

A fundamental feature that Alzheimer’s and Parkinson’s diseases share with nearly all other age-related neurological disorders is the accumulation of clumps of proteins, referred to as amyloid fibrils. These fibrils are typically correlated with the progressive loss of brain function and nerve cell death. Analysis of inherited forms of the diseases indicates that the amyloid somehow cause the diseases, but at present it is still not clear whether these large protein clumps are indeed the toxic agents that kill nerve cells. There is increasing evidence that the smaller soluble oligomers that represent intermediates in amyloid fibril formation are more toxic to cells. Here we propose to study which forms of the proteins capable of amyloid fibril formation are responsible for disrupting the integrity of cellular membranes. Nerve cells require intact cellular membranes to support their function in electrical signaling and survival; therefore membrane destabilization may represent the common mechanism for why amyloids cause these diseases.

Our ability to characterize the molecular details of the interaction of proteins and peptides with membranes has been dramatically improved with the recent development of electron paramagnetic resonance (EPR) spectroscopy as a probe of membrane protein structure. The structure of the membrane- associated protein and details of their interaction with the membrane lipids will be elucidated. In summary, it is the goal of this proposal to deduce how nerve cells die in Alzheimer’s and Parkinson’s diseases using novel and highly interdisciplinary approaches.