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.

项目摘要亨廷顿氏病（HD）是一种常染色体显性神经退行性疾病，没有疾病存在修改疗法。临床符号包括进行性非自愿运动，精神病迹象，认知能力下降，寿命缩短。目前尚无可用的“神经保护”疗法修改HD的疾病过程。尽管正常的亨廷顿（HTT）功能尚不完全了解，但突变体 HTT（MHTT）与线粒体功能障碍有关，因为它破坏了能量功能，导致线粒体蛋白运输受损，线粒体动力学和蛋白质的中断进口。线粒体功能障碍已成为HD疾病进展的关键确定剂。因此，反对MHTT诱导的线粒体功能障碍正在成为治疗的目标毁灭性的条件。正确的线粒体功能需要精心策划的体内稳态和谨慎线粒体酶活性的调节。赖氨酸乙酰化是一种高度调节的翻译后修改大量线粒体蛋白会受到可逆歌词乙酰化以及这些蛋白质的功能受其乙酰化状态调节。 Sirt3曾经被证明是主要的线粒体脱乙酰基酶，并控制全球的乙酰化水平线粒体蛋白。当前应用的目的是确定SIRT3是否可以保护反对MHTT诱导的线粒体功能障碍和体内神经变性，并揭示基础 HD中SIRT3介导的神经保护的分子机制。为了实现这一目标，我们将测试 SIRT3调节线粒体乙酰基组并维持线粒体代谢的假设通过以下特定目的对MHTT响应稳态。在特定目标1中，我们将确定疾病发作之前或之后SIRT3的过表达是否会延迟疾病发作和缓慢 HD小鼠模型中的疾病进展。在特定目标2中，我们将研究分子机制通过结合假设驱动的方法和无偏的乙酰基组方法。这些特定目标的成功完成将有助于对线粒体保真度蛋白SIRT3在HD和线粒体中的作用的机械理解功能障碍，可能鉴定出对HD的药物操纵的新靶标的潜在鉴定。