Synaptic vesicle changes in synucleinopathies

突触小泡在突触核蛋白病中的变化

基本信息

批准号：
10500910
负责人：
Jacqueline Burre
金额：
$ 46.4万
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：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10500910
关键词：
Affect Age Age-Months Aging Alzheimer&apos s disease related dementia Basic Science Binding Biochemical Biology Brain Central Nervous System Diseases Complex Conflict (Psychology)Data Disease Duct (organ) structure Electron Microscopy Equilibrium Fostering Foundations Glutamates Human In Vitro Lewy Body Dementia Link Lipid Bilayers Lipid Binding Lipids Liposomes Maps Mediating Medical Membrane Mission Molecular Molecular Chaperones Mus Mutation Neurotransmitters Organelles Outcome Parkinson Disease Parkinson&apos s Dementia Pathogenicity Pathologic Pathology Patients Physiological Positioning Attribute Precipitating Factors Proteins Proteomics Public Health Publishing Regulatory Element Research Resolution SNAP receptor Synapses Synaptic Vesicles Testing Therapeutic Intervention Time Transgenes Translational Research United States National Institutes of Health Work age related alpha synuclein base brain tissue cell type cholinergic density early onset gamma-Aminobutyric Acid innovation link protein lipidomics motor symptom mouse model mouse synuclein alpha nervous system disorder neurotransmitter release novel presynaptic synuclein synucleinopathy

项目摘要

The central objective of this proposal is to quantify changes in synaptic vesicle (SV) pools and composition over aging and in Alzheimer's Disease Related Dementias such as Lewy body dementia and Parkinson’s dis-ease. SVs mediate neurotransmitter release at the synapse. Their abundance and uniform size have enabled extensive biochemical studies, and ~15% of SV proteins have been linked to CNS diseases, with numerous of them in Alzheimer's Disease Related Dementias and Parkinson’s disease. Yet, no study has analyzed SV sub-types, defined by their vesicular neurotransmitter transporter, or changes in SV composition or pools with aging and in Parkinson’s disease and Alzheimer's Disease Related Dementias such as Lewy body dementia. Most SV proteins are low abundant, with a copy number of <1 per SV. This suggests molecular and functional SV diversity, necessitating a thorough and mechanistic analysis of SV pools and composition. α-Synuclein (αSyn) exists in a SV-bound and a cytosolic state, exchanging between these pools in a dynamic equilibrium. SV-bound αSyn mediates its physiological functions at the synapse. Aggregation of αSyn is a pathological hallmark of Parkinson’s disease, Lewy body dementia and other Alzheimer's Disease Related Dementias, and a large fraction of αSyn aggregates occurs in presynaptic boutons. Pathology has been suggested to be associated with altered αSyn:lipid interactions, and several SV proteins are linked to Parkinson’s disease, Lewy body dementia and other Alzheimer's Disease Related Dementias. Thus, changes in SV lipids or proteins could alter binding of αSyn to SVs. The hypothesis is that reduced SV-binding of αSyn is a precipitating factor for αSyn-linked pathology, and that changes in SV numbers, protein and/or lipid composition account for the reduction in αSyn binding. Guided by our strong preliminary data, revealing reduced SV-binding of αSyn in two Parkinson’s disease mouse models and in brain tissue of Parkinson’s disease and Lewy body dementia patients in addition to an age-dependent reduction of SV density in our humanized αSyn mouse model, this hypothesis will be tested in two specific aims: 1) Determine changes in synaptic vesicle numbers and pools, and 2) Determine changes in SV composition. The study is expected to provide a systematic understanding of the changes in SV pools and composition during aging and in Parkinson’s disease, Lewy body dementia and other Alzheimer's Disease Related Dementias, which lays the foundation to dive further into mechanistic studies. This work is innovative because it will generate high-resolution maps of SVs of different neurotransmitter subtypes over the course of aging and αSyn-linked pathology. The work is significant because it (1) determines for the first time changes in SV composition during aging, (2) determines for the first time the composition of SV subtypes, (3) has important implications for Parkinson’s disease, Lewy body dementia and other Alzheimer's Disease Related Dementias, (4) may provide clues towards cell-type specific vulnerability in Alzheimer's Disease Related Dementias such as Lewy body dementia and in Parkinson’s disease.

量化突触囊泡（SV）池的变化和成分的中心目标，以及阿尔茨海默氏症的疾病中的痴呆症，例如Lewy身体痴呆症和帕金森氏症的大小。相关的痴呆症和帕金森氏病较低，每SV的拷贝数<1。帕金森氏症的痴呆症和其他阿尔茨海默氏症的痴呆症的标志是αsyn的痴呆症，αsyn在突触前的boutons中，以及几种SV蛋白红色诱导的αSyn的SV结合是一种连接的病理学，SV数量，蛋白质和/或脂质组成的变化是αsyn结合的重新构成的。帕金森氏病和路易痴呆症患者的鼠标和脑组织中，除了我们的人源化α-卵形鼠类中的Ange依赖性SV密度的重新依赖，此外还将以两个具体的目的进行测试：1）确定突触囊泡数量和突触的变化池，2）确定SV组成的变化。在机械研究中进一步研究这项工作，因为它将在整个过程中产生不同神经递质亚型的SV的地图。，（2）确定亚型的组成，（3）对帕金森氏病，路易人的痴呆症和其他与Heimer疾病相关的痴呆症的重要性很重要，（4）可能会提供有关阿尔茨海默氏病相关的细胞型特异性脆弱性的线索例如路易的身体痴呆症和帕金森氏病。