Mechanisms of Synaptic Dysfunction in Parkinson s and Other Synuclein-Linked Diseases

项目摘要

PROJECT ABSTRACT Aggregation of α-synuclein throughout the neuron, including at synapses, is a pathological hallmark of Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and variants of Alzheimer’s disease (AD). Synaptic aggregation of α-synuclein is strongly associated with cognitive deficits and dementia in PD and DLB. The long-term goal of this project is to identify the cellular and molecular mechanisms that give rise to α-synuclein-induced synaptic deficits and to develop strategies for reversing them. While it is generally agreed that α-synuclein accumulation at synapses impairs synaptic vesicle trafficking, the underlying mechanisms remain unclear, preventing the development of treatments for improving synaptic function in PD and DLB. Over the last decade, we developed and implemented lamprey reticulospinal synapses as a new model for studying how α-synuclein accumulation impacts synapse structure and function. Our lab was the first to discover that acutely introducing excess α-synuclein to synapses, mimicking increased expression in PD and DLB, inhibits synaptic vesicle endocytosis. This result was subsequently corroborated at mammalian synapses. We then discovered that different molecular species of α-synuclein (e.g. monomers vs. dimers) cause distinct impacts on endocytosis, emphasizing the need to understand how each species affects synaptic vesicle trafficking and the underlying mechanisms. Experiments proposed here will significantly advance the field by: determining how post-translational modifications of α-synuclein alter its effects at synapses (Aim 1); identifying how α-synuclein oligomers purified from human PD and DLB brains affect synapses (Aim 2); and examining the underlying mechanisms with selective inhibitors of α-synuclein membrane binding and oligomerization (Aim 3). The project is significant because it will substantially increase our understanding of the impacts of excess α-synuclein on synapses, including pathology-associated strains, and it will provide initial testing of α-synuclein inhibitors with therapeutic potential while also probing the molecular mechanisms.