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The impact of synaptic vesicle-binding of alpha-synuclein on neuron function and neuropathology

α-突触核蛋白突触小泡结合对神经元功能和神经病理学的影响

基本信息

批准号：
10665732
负责人：
Jacqueline Burre
金额：
$ 43.9万
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：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10665732
关键词：
Acceleration Area Basic Science Behavior Behavioral Assay Binding Biochemical Biochemistry Biological Brain Cells Cellular biology Cessation of life Cognitive Complex Data Dependence Development Disease Disease Progression Dose Electrostatics Exhibits Fostering Functional disorder Genes Genetic Polymorphism Histologic Hydrophobic Interactions Impairment In Vitro Injections Knockout Mice Lentivirus Vector Lewy Bodies Lewy Body Dementia Link Liposomes Location Mediating Medical Membrane Mission Molecular Molecular Chaperones Motor Mus Mutation Nerve Neurologic Neurons Onset of illness Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathology Patients Physiological Process Public Health Published Comment Publishing Rattus Recombinants Research SNAP receptor Substantia nigra structure Synapses Synaptic Vesicles System Techniques Testing Therapeutic Intervention Toxic effect Transfection Translational Research United States National Institutes of Health Variant Vesicle Work alpha synuclein biophysical techniques brain tissue dopaminergic neuron improved in vivo innovation insight interdisciplinary approach loss of function mouse model mutant nervous system disorder neuronal survival neuropathology neurotoxicity neurotransmitter release nigrostriatal degeneration nonhuman primate novel novel therapeutic intervention premature protein purification rational design single molecule synuclein synucleinopathy tool trafficking vesicular release

项目摘要

Alpha-synuclein (aSyn) 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 aSyn triggers neuropathology through a gain-of-toxic-function mechanism, and approaches to eliminate aSyn represent an active area of research for treatment. Yet, aSyn aggregation may also endanger neurons by removing aSyn from synaptic vesicles (its physiologically relevant intracellular location) and thereby causing loss-of-function. Through its synaptic vesicle-bound state, aSyn regulates synaptic vesicle trafficking, and chaperones SNARE-complex assembly to maintain neurotransmitter release. Thus, removing aSyn from neurons may not be protective, but detrimental. The objective in this application is to determine the impact of synaptic vesicle-binding of aSyn on aSyn function and neuron survival, using rationally designed variants of aSyn that stabilize synaptic vesicle-binding. The central hypothesis is that stabilizing binding of aSyn on synaptic vesicles reduces aSyn 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 aSyn on SNARE-complex assembly; 2) Assess the effect of increased synaptic vesicle-binding of aSyn 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 aSyn knockout mice to assess effects of mutant aSyn 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 aSyn 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 aSyn 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 aSyn 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 aSyn to disease pathogenesis, and 4) have translational importance for the development of new treatment strategies aimed at stabilizing synaptic vesicle-bound αSyn.

α -突触核蛋白（aSyn）病理与突触核蛋白病有关，包括帕金森病和路易体

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Synaptic vesicle binding of α-synuclein is modulated by β- and γ-synucleins.

DOI：
10.1016/j.celrep.2022.110675
发表时间：
2022-04-12
期刊：
CELL REPORTS
影响因子：
8.8
作者：
Carnazza, Kathryn E.;Komer, Lauren E.;Xie, Ying Xue;Pineda, Andre;Briano, Juan Antonio;Gao, Virginia;Na, Yoonmi;Ramlall, Trudy;Buchman, Vladimir L.;Eliezer, David;Sharma, Manu;Burre, Jacqueline
通讯作者：
Burre, Jacqueline

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