Mitochondrial SIRT3 in Huntington's disease

亨廷顿病中的线粒体 SIRT3

基本信息

批准号：
9334324
负责人：
Wenzhen Duan
金额：
$ 20.44万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9334324
关键词：
Acetylation Activities of Daily Living Address Affective Age Attenuated Autopsy Body Weight Brain Brain Diseases Brain region CAG repeat Cerebellum Clinical Cognition Corpus striatum structure Cultured Cells Data Deacetylase Disease Disease Progression Disease model Enzymes Equilibrium Exons Gene Delivery Genes Gliosis Goals Homeostasis Human Huntington Disease Huntington gene Impaired cognition Impairment Individual Interruption Involuntary Movements Longevity Lysine Magnetic Resonance Imaging Measures Mediating Membrane Metabolic Mitochondria Mitochondrial Proteins Modification Molecular Moods Motor Mus Nerve Degeneration Neurodegenerative Disorders Neurons Onset of illness Organelles Pathogenesis Pathology Pharmacology Phenotype Post-Translational Protein Processing Prosencephalon Protein Import Proteins Proteomics Regulation Reporting Research Respiration Role Symptoms Tamoxifen Testing Toxic effect Transgenes Transgenic Organisms Viral base brain tissue brain volume cerebral atrophy functional loss in vivo insight mitochondrial dysfunction mouse model mutant neuropathology neuroprotection neurotoxicity novel overexpression prevent protective effect protein function protein transport response small molecule therapeutic target

项目摘要

PROJECT SUMMARY Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder for which no disease modifying therapy exists. Clinical symptoms include progressive involuntary movement, psychiatric signs, cognitive decline, and a shortened lifespan. There is no currently available “neuroprotective” therapy to modify the disease course of HD. Although normal huntingtin (Htt) function is not fully understood, mutant HTT (mHtt) has been associated with mitochondrial dysfunction because it disrupts energetic function, leads to impaired mitochondrial protein trafficking and interruption of mitochondrial dynamics and protein import. Mitochondrial dysfunction has emerged as a key determinant of the disease progression in HD. Therefore counteracting mHtt-induced mitochondrial dysfunction is emerging as a target of treatment for this devastating condition. Proper mitochondrial function requires well-orchestrated homeostasis and careful regulation of the activity of mitochondrial enzymes. Lysine acetylation is a highly regulated posttranslational modification in which a substantial number of mitochondrial proteins are subject to reversible lysine acetylation, and the function of these proteins is regulated by its acetylation status. SIRT3 has been demonstrated as a dominant mitochondrial deacetylase and controls acetylated levels of global mitochondrial proteins. The goal of the current application is to determine whether SIRT3 can protect against mHtt-induced mitochondrial dysfunction and neurondegeneration in vivo and reveal the underlying molecular mechanisms of SIRT3-mediated neuroprotection in HD. In pursuit of this goal, we will test the hypothesis that SIRT3 regulates mitochondrial acetylome and maintains mitochondrial metabolic homeostasis in response to mHtt through the following specific aims. In Specific Aim 1, we will determine whether overexpression of SIRT3 before or after the onset of disease will delay disease onset and slow disease progression in HD mouse models. In Specific Aim 2, we will investigate the molecular mechanisms underlying the SIRT3-medicated neuroprotection in HD by combining hypothesis-driven approach and unbiased acetylome approach. Successful completion of these specific aims will contribute to the mechanistic understanding of the role of a mitochondrial fidelity protein, SIRT3, in HD and mitochondrial dysfunction with potential identification of novel targets for pharmacologic manipulation for HD.

项目概要亨廷顿病 (HD) 是一种常染色体显性神经退行性疾病，目前尚无疾病临床症状包括进行性不自主运动、精神体征、认知能力下降和寿命缩短目前尚无可用的“神经保护”疗法。改变HD的病程虽然正常的亨廷顿蛋白（Htt）功能尚未完全了解，但是突变体。 HTT (mHtt) 与线粒体功能障碍有关，因为它会破坏能量功能，导致线粒体蛋白质运输受损以及线粒体动力学和蛋白质中断线粒体功能障碍已成为 HD 疾病进展的关键决定因素。因此，对抗 mHtt 诱导的线粒体功能障碍正在成为该疾病的治疗目标适当的线粒体功能需要精心协调的体内平衡和小心。线粒体酶活性的调节是高度调节的翻译后酶。大量线粒体蛋白受到可逆赖氨酸的修饰 SIRT3 乙酰化，并且这些蛋白质的功能受其乙酰化状态调节。被证明是一种主要的线粒体脱乙酰酶，并控制全局的乙酰化水平当前应用的目标是确定 SIRT3 是否可以保护线粒体。对抗 mHtt 诱导的线粒体功能障碍和体内神经变性，并揭示潜在的机制 SIRT3 介导的 HD 神经保护的分子机制为了实现这一目标，我们将测试 SIRT3 调节线粒体乙酰基并维持线粒体代谢的假设在具体目标 1 中，我们将确定通过以下具体目标来响应 mHtt 的稳态。在疾病发作之前或之后过度表达 SIRT3 是否会延迟疾病发作并减慢在 HD 小鼠模型中，我们将研究其分子机制。通过结合假设驱动的方法和公正的乙酰组方法的成功完成将有助于实现这些具体目标。线粒体保真蛋白 SIRT3 在 HD 和线粒体中的作用的机制理解功能障碍与潜在的 HD 药理操作新靶标的鉴定。