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Mitochondrial Amyloid Beta accumulation via non-canonical receptor Tom22

通过非经典受体 Tom22 的线粒体β淀粉样蛋白积累

基本信息

批准号：
9976158
负责人：
Hongjin Zheng
金额：
$ 41.56万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2020-04-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9976158
关键词：
3-Dimensional Affect Alzheimer&apos s Disease Alzheimer&apos s disease patient Amyloid beta-Protein Biochemical Biological Process Biology Biophysics Brain Cells Cellular biology Chemistry Complex Data Disease Event Functional disorder Future Goals In Vitro Knowledge Laboratories Mediating Membrane Proteins Methods Mitochondria Mitochondrial Proteins Modeling Molecular Mutagenesis NMR Spectroscopy Organelles Outcome Outer Mitochondrial Membrane Pathogenesis Pathologic Patients Peptides Play Preventive Process Protein Biochemistry Protein Import Protein Precursors Reporting Role Signal Transduction Structure Structure-Activity Relationship Therapeutic X-Ray Crystallography abeta accumulation biophysical techniques common symptom drug development improved mitochondrial dysfunction mouse model neurodegenerative dementia novel prevent protein complex receptor small molecule structural biology success three dimensional structure tool uptake

项目摘要

Compelling evidence has suggested that mitochondrial dysfunction is an early event in Alzheimer’s Disease (AD) pathophysiology. This mitochondrial dysfunction is closely related to the elevated level of intracellular Aβ, which appears to be accumulated within mitochondria in the brains of both Alzheimer’s patients and mouse models. How mitochondria actively accumulate Aβ is not clear, and thus represents a large gap of knowledge in the field. We aim to understand the very first step of this accumulation process by studying the detailed molecular mechanism of substrate/receptor interaction. We have identified that Aβ is recognized by a non-canonical receptor, Tom22, within the mitochondrial protein import machinery. In this proposal, we expect to perform two related but independent specific aims to reach that goal. 1). We will characterize the interaction between Aβ and Tom22 receptor in details, by biophysical, biochemical and cell biology tools; 2). We expect to determine three dimensional atomic structures of Tom22 and Tom22/Aβ complex. The functional and structural information gained here are expected to reveal detailed molecular mechanism underlining the detrimental process of mitochondrial uptake of Aβ peptides, and thus provide novel models to screen molecules that are capable of disrupting the specific Tom22/Aβ interaction. Thus, the outcome of this proposal is expected to have important positive impact in treating mitochondrial dysfunction caused by Aβ in AD.

令人信服的证据表明，线粒体功能障碍是阿尔茨海默病的早期事件