Neuronal Mechanisms of Copper Transport and Toxicity

铜转运和毒性的神经机制

基本信息

批准号：
10366543
负责人：
Victor Faundez
金额：
$ 39.07万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10366543
关键词：
3xTg-AD mouse Address Administrative Supplement Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid Animal Model Apolipoprotein E Astrocytes Automobile Driving Award Biochemical Brain Categories Cause of Death Cell Line Cell membrane Cells Cholesterol Cholesterol Homeostasis Cognition Copper Data Defect Dementia Disease Drosophila genus ENG gene Event Functional disorder Gene Expression Genes Genetic Genetic Risk Homeostasis Impairment Inner mitochondrial membrane Leukemic Cell Link Mammalian Cell Maps Measures Medical Genetics Membrane Messenger RNA Microglia Mitochondria Mitochondrial Proteins Modeling Molecular Chaperones Mus Mutant Strains Mice Mutation Nerve Degeneration Neurons Pathogenesis Pathogenicity Pathology Pathway interactions Predisposition Process Production Protein Precursors Proteins Research Respiratory Chain Rest Risk SPI1 gene Synapses Testing Toxic effect United States United States National Institutes of Health Up-Regulation Work amyloid peptide brain cell citrate carrier complex IV experimental study falls genetic risk factor genome-wide interest lipidomics loss of function mitochondrial dysfunction mitochondrial membrane mouse model mutant neuroblastoma cell novel response risk variant uptake

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is a debilitating form of dementia, and a leading cause of death in the United States. Dominant pathogenesis models postulate that initiating factor are either the aberrant processing of the Alzheimer’s precursor protein (APP), which leads to the accumulation of amyloid peptide toxic species in brain or the expression of an Alzheimer’s disease associated allele, APOE4. In these models, mitochondria respond to the toxicity of amyloid peptides or APOE4 rather than mitochondria driving pathogenesis. Here we explore a novel mitochondrial mechanism initiated by genetic defects in copper delivery mechanisms to the mitochondria (ATP7A, SLC31A1, COX17), the inner mitochondrial membrane mitochondrial citrate transporter SLC25A1 and its interacting protein, NDUFS3. The latter a gene associated to a genetic risk loci in Alzheimer’s disease. We found that the main defect downstream of mutations in these genes that end affecting mitochondria is an upregulation of cholesterol synthesis pathways, cholesterol, and the expression of APOE. These findings have profound implications as they suggest that upregulation of cholesterol and APOE, key risks factor for Alzheimer’s disease, are initiated by a genetic defect affecting mitochondria. Our model challenges the current canonical view that mitochondrial dysfunction is a terminal link in a chain of events ending in synapse dysfunction and Alzheimer’s disease. We envision our mitochondria-driven pathogenesis model as a powerful addition rather than a replacement of the current paradigm of amyloid peptide- or APOE4-driven Alzheimer’s pathogenesis. We posit that the mitochondrion acting as initiator of pathology is an important concept because it argues that disease would unravel in a positive feed-forward circle integrating amyloid peptides, APOE4, cholesterol, and mitochondria. We will test this hypothesis with mouse mutants that impair copper delivery to mitochondria and stablished animal models of Alzheimer’s disease with clinical and genetic validity.

项目概要阿尔茨海默病 (AD) 是一种使人衰弱的痴呆症，也是美国的一个主要原因。主要发病机制模型假设起始因素是细胞的异常加工阿尔茨海默病前体蛋白（APP），导致淀粉样肽有毒物质在大脑中积累或阿尔茨海默病相关等位基因 APOE4 的表达在这些模型中，线粒体做出反应。淀粉样肽或 APOE4 的毒性而不是线粒体驱动的发病机制在此我们探讨。通过铜向线粒体输送机制的遗传缺陷而启动的新型线粒体机制（ATP7A、SLC31A1、COX17）、线粒体内膜线粒体柠檬酸转运蛋白 SLC25A1 和其相互作用蛋白 NDUFS3 是与阿尔茨海默病遗传风险位点相关的基因。发现最终影响线粒体的这些基因突变下游的主要缺陷是胆固醇合成途径、胆固醇和 APOE 表达的上调。具有广泛的影响，因为它们表明胆固醇和 APOE 的上调是阿尔茨海默病的关键危险因素疾病是由影响线粒体的遗传缺陷引发的，我们的模型挑战了当前的规范。认为线粒体功能障碍是导致突触功能障碍的一系列事件中的一个终端环节我们设想线粒体驱动的发病机制模型是一个强大的补充。而不是取代目前淀粉样肽或 APOE4 驱动的阿尔茨海默病发病机制的范例。假设线粒体作为病理学的引发者是一个重要的概念，因为它认为疾病将在整合淀粉样肽、APOE4、胆固醇和我们将用损害铜向线粒体输送的小鼠突变体来测试这一假设。稳定的阿尔茨海默病动物模型具有临床和遗传有效性。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ratiometric two-photon microscopy reveals attomolar copper buffering in normal and Menkes mutant cells.

比率双光子显微镜揭示了正常细胞和 Menkes 突变细胞中的阿摩尔铜缓冲。

DOI：
发表时间：
2019
期刊：
影响因子：
11.1
作者：
Morgan, M Thomas;Bourassa, Daisy;Harankhedkar, Shefali;McCallum, Adam M;Zlatic, Stephanie A;Calvo, Jenifer S;Meloni, Gabriele;Faundez, Victor;Fahrni, Christoph J
通讯作者：
Fahrni, Christoph J

Trafficking mechanisms of P-type ATPase copper transporters.

P 型 ATP 酶铜转运蛋白的运输机制。

DOI：
10.1016/j.ceb.2019.02.009
发表时间：
2019-08-01
期刊：
Current opinion in cell biology
影响因子：
7.5
作者：
Cortnie L. Hartwig;Stephanie A. Zlatic;Melissa Wallin;A. Vrailas;C. Fahrni;V. Faundez
通讯作者：
V. Faundez

Cdh1-APC Regulates Protein Synthesis and Stress Granules in Neurons through an FMRP-Dependent Mechanism.

Cdh1-APC 通过 FMRP 依赖性机制调节神经元中的蛋白质合成和应激颗粒。

DOI：
发表时间：
2020-05-22
期刊：
影响因子：
5.8
作者：
Valdez;Lai, Austin;Shi, Liang;Lancaster, Carly L;Gokhale, Avanti;Faundez, Victor;Bassell, Gary J
通讯作者：
Bassell, Gary J

Sulfur- and phosphorus-standardized metal quantification of biological specimens using inductively coupled plasma mass spectrometry.

使用电感耦合等离子体质谱法对生物样本进行硫和磷标准化金属定量。

DOI：
发表时间：
2022-06-17
期刊：
影响因子：
0
作者：
Lane, Alicia;Gokhale, Avanti;Werner, Erica;Roberts, Anne;Freeman, Amanda;Roberts, Blaine;Faundez, Victor
通讯作者：
Faundez, Victor

Protocol for Immuno-Enrichment of FLAG-Tagged Protein Complexes.

FLAG 标记蛋白复合物的免疫富集方案。