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Structural basis and physiological consequences of alpha-Synuclein binding to neurexin 1beta

α-突触核蛋白与神经毒素 1β 结合的结构基础和生理学后果

基本信息

批准号：
10677814
负责人：
Elizabeth Rhoades
金额：
$ 57.45万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677814
关键词：
Acetylation Affinity Automobile Driving Binding Brain Cell membrane Cells Characteristics Coculture Techniques Communities Complex Data Deposition Disease Fluorescence Resonance Energy Transfer Future Genes Global Change Glycoproteins Goals Grain In Vitro Inherited Kinetics Lewy Bodies Link Mass Spectrum Analysis Measures Mediating Mediator Membrane Proteins Modeling Modification Molecular Molecular Structure N-terminal Neurodegenerative Disorders Neurons Parkinson Disease Pathologic Pathology Persons Physiological Play Polysaccharides Post-Translational Protein Processing Process Proteins Reporting Research Resolution Role Single Nucleotide Polymorphism Specificity Structure Surface Synapses System Testing Therapeutic Variant Work alpha synuclein design extracellular glycosylation in vivo insight live cell imaging monomer mutant novel pharmacologic presynaptic protein aggregation receptor small molecule small molecule therapeutics success synaptic function synaptogenesis synergism therapeutically effective transmission process uptake

项目摘要

Project Summary/Abstract α-Synuclein is a small, soluble neuronal protein that is the primary component of the Lewy body aggregates that are the hallmark of Parkinson's disease. While the mechanistic details are not yet well-understood, emerging evidence suggests that cell-to-cell transmission of toxic forms of α-Synuclein is the basis of disease propagation. Our lab has recently identified complex N-linked glycans as mediators of cellular internalization of both monomer and aggregate forms of α-Synuclein bearing an N-terminal acetyl group, a physiological modification of the protein. We specifically identified the neuronal glycoprotein neurexin 1β as capable of driving internalization of α-Synuclein in a glycan-dependent manner. The goal of our proposed research is to characterize the structural basis of α-Synuclein binding to neurexin 1β, the role of both N-terminal acetylation and glycosylation in conferring specificity in this interaction, and determine the molecular mechanisms resulting cellular internalization of α-Synuclein following binding neurexin 1β. Our hypothesis is that cell-to-cell transmission of αS is dependent on interactions with neurexin 1β and that the selectivity in these interactions is dependent on transient structural changes in α-Synuclein conferred by the N-terminal acetyl group. To investigate this hypothesis, we have developed three specific aims with the following goals: determine the structural features of α-Synuclein bound to neurexin 1β, including defining a minimal α-Synuclein construct required for binding (Aim 1); determine the mechanisms by which binding to neurexin 1β results in cellular internalization of α-Synuclein (Aim 2); and understand the functional impact of α-Synuclein binding to neurexin 1β (Aim 3). To achieve these goals, we will carry out in vitro coarse grain and high resolution structural characterization of α-Synuclein:neurexin 1β complexes and use live-cell imaging to quantify internalization of α-Synuclein and the ability of internalized α-Synuclein to seed aggregation of endogenous α-Synuclein. We will contrast WT monomer, PD-associated point mutants and fibrillar forms of α-Synuclein. Through this research we expect to characterize key interactions involved in propagation of α-Synuclein pathology in Parkinson's disease, as well as to gain insight into the structural features of α-Synuclein:neurexin 1β complexes. Ultimately, the characterization of α-Synuclein: neurexin 1β interactions carried out through our studies may provide a new target for Parkinson's disease treatment and serve as the basis identifying novel small molecule therapeutics.

项目总结/文摘