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Changes in synaptic vesicle-binding of alpha-synuclein in the central and enteric nervous system

中枢和肠神经系统中α-突触核蛋白突触小泡结合的变化

基本信息

批准号：
10527040
负责人：
Jacqueline Burre
金额：
$ 6.44万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10527040
关键词：
Area Basic Science Behavioral Assay Binding Biochemical Biological Brain Cells Complex Data Development Disease Enteric Nervous System Fostering Functional disorder Histologic In Vitro Injections Knockout Mice Lentivirus Vector Lewy Body Dementia Link Location Medical Mission Molecular Molecular Chaperones Mus Neurons Parkinson Disease Pathogenesis Pathology Physiological Public Health Published Comment Research SNAP receptor Substantia nigra structure Synaptic Vesicles System Techniques Testing Therapeutic Intervention Toxic effect Translational Research United States National Institutes of Health Variant Work alpha synuclein biophysical techniques improved in vivo innovation insight interdisciplinary approach loss of function mouse model mutant nervous system disorder neuropathology neurotoxicity neurotransmitter release novel rational design single molecule synucleinopathy tool trafficking treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Alpha-synuclein (αSyn) pathology is linked to synucleinopathies including Parkinson's disease and Lewy body dementia, but the underlying disease mechanisms remain poorly understood. The prevalent viewpoint has emerged that aggregation of αSyn triggers neuropathology through a gain-of-toxic-function mechanism, and approaches to eliminate αSyn represent an active area of research for treatment. Yet, αSyn aggregation may also endanger neurons by removing αSyn from synaptic vesicles (its physiologically relevant intracellular location) and thereby causing loss-of-function. Through its synaptic vesicle-bound state, αSyn regulates synaptic vesicle trafficking, and chaperones SNARE-complex assembly to maintain neurotransmitter release. Thus, removing αSyn from neurons may not be protective, but detrimental. The objective in this application is to determine the impact of synaptic vesicle-binding of αSyn on αSyn function and neuron survival, using rationally designed variants of αSyn that stabilize synaptic vesicle-binding. The central hypothesis is that stabilizing binding of αSyn on synaptic vesicles reduces αSyn toxicity and pathology. Guided by strong preliminary data, this hypothesis will be tested in three specific aims: 1) Determine the effect of increased synaptic vesicle-binding of αSyn on SNARE-complex assembly; 2) Assess the effect of increased synaptic vesicle-binding of αSyn on synaptic vesicle cycling; and 3) Test if increased synaptic vesicle-binding of αSyn rescues neurotoxicity and pathology in vivo. Under the first aim, SNARE-complex assembly will be quantified in vivo and in vitro, using cell biological and biochemical techniques. Under the second aim, αSyn multimerization, synaptic vesicle pools and clustering, and synaptic vesicle cycling will be quantified, using cell biological, biochemical and biophysical techniques. Under the third aim, mouse models will be generated by stereotactic injections of lentiviral vectors into the substantia nigra of αSyn knockout mice to assess effects of mutant αSyn variants on αSyn-induced toxicity and pathology, using behavioral assays on mice and biochemical, histological and ultrastructural analyses on injected brains. The study is expected to show improved αSyn function and delayed pathology upon stabilization of synaptic vesicle-binding of αSyn. This research is innovative because it 1) tests the novel hypothesis that stabilizing synaptic vesicle-bound αSyn reduces αSyn pathology, 2) creates new tools to study function and dysfunction of αSyn, and 3) uses a multidisciplinary approach to test our hypothesis from single molecules and cellular systems to live mice. This work is significant, because it will 1) clarify the importance of synaptic vesicle-binding of αSyn for neuron function, 2) provide new insights into the molecular mechanism of synaptic vesicle-binding of αSyn, 3) uncover the contribution of loss-of-function of αSyn to disease pathogenesis, and 4) have translational importance for the development of new treatment strategies aimed at stabilizing synaptic vesicle-bound αSyn.

项目总结/文摘