Abnormal accumulation and misfolding of a-synuclein (SYN) and amyloid-p protein (A|3) may be at the rootof a wide spectrum of neurodegenerative disorders leading to dementia, parkinsonism, and autonomicdysfunction. These disorders, called Lewy body diseases, account for the great majority of cases withcombined dementia and movement disorders in the U.S. Previously, we showed that A(31-42 enhances theaggregation and toxicity of SYN. In the previous funding period, we focused on the involvement of thelysosomal-endosomal pathway in the copathogenic synergism between A|31-42 and SYN. Our studiesshowed that A|31-42 and SYN promote neurodegeneration by interfering with autophagy and reducing theclearance of other neuronal proteins, such as parkin and cytoskeletal proteins. In this proposal, we we willtest the hypothesis that A(31-42 activates calcium-dependent proteases in a glutamate receptor-dependentmanner, which, in turn, results in the generation of SYN fragments that promote the formation of pathogenicSYN oligomers. We further hypothesize that this pathogenic cascade is engaged most readily in limbic andstriatal neurons, which are particularly vulnerable to Lewy body diseases. To test these hypotheses, wepropose the following specific aims.
Aim 1 : To determine if the coexpression of APP/A|3 and SYN affects thevulnerability of specific neuronal populations in the hippocampus and striatum (in collaboration with Project 5and Cores C, D).
Aim 2 : To determine, in cultured neurons, if the copathogenic effects of A(3 and SYNdepend on glutamate receptors and SYN cleavage (with Projects 1-3 and Cores B and D).
Aim 3 : Todetermine by genetic ablation whether the copathogenic effects of A[3 and SYN depend on the activation of aspecific glutamate receptor in vivo (with Project 1).
Aim 4 : To determine if the impairments of transgenicmice expressing SYN and A(3 can be prevented or ameliorated by inhibiting glutamate receptors orpromoting A(3 clearance (with Project 5 and Cores C and D). In collaboration with other components of theprogram, this project will help elucidate mechanisms of selective vulnerability and determine if interventionsaimed at A|3 or A|3-dependent pathways might be useful in preventing or treating Lewy body diseases.
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