Mitochondrial Fragmentation and Neurodegeneration in Huntington's Disease

亨廷顿病中的线粒体断裂和神经变性

基本信息

批准号：
9757824
负责人：
P. Hemachandra Reddy
金额：
$ 37.83万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9757824
关键词：
Address Affect Autopsy Axonal Transport Bacterial Artificial Chromosomes Behavior Blood - brain barrier anatomy Brain Brain region Cell Line Cell Survival Cells Cerebellum Chimeric Proteins Corpus striatum structure Disease Progression Dose Dynamin Free Radicals Genes Genetic Glucose Goals Guanosine Triphosphate Phosphohydrolases HDAC1 gene Half-Life Heterozygote Huntington Disease Huntington gene Impairment Injury Kidney Knock-in Knock-in Mouse Knock-out Lipid Peroxidation Mitochondria Modeling Molecular Morphology Mus Mutant Strains Mice Nerve Degeneration Neuronal Dysfunction Neurons OPA1 gene Outcomes Research Oxygen Pathogenesis Patients Pharmacology Phenotype Plasma Production Protein Dynamics Proteins Reperfusion Injury Research Research Personnel Stable Disease Structure Synapses Testing Therapeutic Therapeutic Human Experimentation Tissues Toxic effect Transgenic Mice Transgenic Organisms Wild Type Mouse base brain tissue cell motility deprivation fusion gene inhibitor/antagonist mitochondrial dysfunction mutant neuron loss neuronal survival oxidative damage polyglutamine prevent synaptic function trafficking

项目摘要

The long-term goal of our research is to develop a rational basis for neuroprotective strategies in order to prevent the onset and to slow the progression of Huntington's disease (HD). Increasing evidence suggests that mutant huntingtin (mHtt) and structural and functional abnormalities of mitochondria are involved in neuronal damage and neuronal loss in HD. Several lines of evidence support the involvement of mitochondrial abnormalities in HD progression and pathogenesis: 1) Increased expression levels of the mitochondrial fission genes Drp1 and Fis1 have been found in postmortem tissues from affected brain regions in HD patients and in striatal and cortical tissues from BACHD transgenic mice; 2) Decreased expression levels of the mitochondrial fusion genes Mfn1, Mfn2, and Opa1 have been found in these same affected regions from HD patients and BACHD transgenic mice; 3) Drp1 interacts with mHtt, and this interaction increases as HD progresses; 4) Increased levels of GTPase Drp1 enzymatic activity have been found in HD neurons; and 5) Decreased mitochondrial mass and motility, reduced anterograde axonal transport of mitochondria, and reduced synaptic viability have been found in primary neurons from BACHD transgenic mice. A therapeutic strategy for HD may involve inhibiting excessive mitochondrial fragmentation. Several mitochondrial fission inhibitors have been identified, including the mitochondria division inhibitor Mdivi1. Mdivi1 has been studied using ischemia/reperfusion injury models, renal injury, and oxygen-glucose deprivation. Findings have revealed that Mdivi1 reduces mitochondrial fission and increases mitochondrial fusion, and maintains mitochondrial function and cell survival. In studies of mitochondrial dynamics in an HD-stable striatal cell line that carries 111 polyQ repeats, researchers found reduced levels of fission genes and increased levels of fusion genes in HDQ111 cells treated with Mdivi1. Mdivi1-treated HDQ111 cells also showed increased mitochondrial function and synaptic activity, suggesting that Mdivi1 protects mitochondrial structure and function, and enhances cell survival. The current application seeks to determine whether a partial reduction of Drp1 in neurons from BACHD transgenic mice and HD knockin mice decreases mitochondrial fission and decreases mHtt-induced toxicity; and whether Mdivi1 in neurons from BACHD transgenic mice and HD knockin mice reduces excessive mitochondrial fragmentation and enhances mitochondrial function and synaptic activity. The outcome of this research will be an elucidation of genetic and pharmacological strategies that may reduce excessive mitochondrial fragmentation and increase neuronal survival and synaptic functions in HD-affected neurons.

我们研究的长期目标是为神经保护建立合理的基础预防亨廷顿病发病并减缓其进展的策略（高清）。越来越多的证据表明突变亨廷顿蛋白 (mHtt) 及其结构和功能线粒体异常与 HD 中的神经元损伤和神经元丢失有关。多项证据支持线粒体异常与 HD 相关进展和发病机制：1）线粒体裂变表达水平增加在 HD 受影响脑区的死后组织中发现了 Drp1 和 Fis1 基因患者以及 BACHD 转基因小鼠的纹状体和皮质组织； 2）减少线粒体融合基因 Mfn1、Mfn2 和 Opa1 的表达水平已被发现 HD 患者和 BACHD 转基因小鼠的这些相同受影响区域； 3）Drp1相互作用与 mHtt，这种相互作用随着 HD 的进展而增加； 4) GTPase Drp1 水平增加在 HD 神经元中发现了酶活性； 5) 线粒体质量减少运动性、线粒体顺行轴突运输减少以及突触活力降低已在 BACHD 转基因小鼠的原代神经元中发现。治疗策略 HD 可能涉及抑制线粒体过度断裂。线粒体的多次裂变已鉴定出多种抑制剂，包括线粒体分裂抑制剂 Mdivi1。 Mdivi1 有使用缺血/再灌注损伤模型、肾损伤和氧-葡萄糖进行研究剥夺。研究结果表明，Mdivi1 减少线粒体裂变并增加线粒体融合，维持线粒体功能和细胞存活。在研究中携带 111 个 PolyQ 重复序列的 HD 稳定纹状体细胞系中的线粒体动力学，研究人员发现，裂变基因水平降低，融合基因水平增加用 Mdivi1 处理的 HDQ111 细胞。 Mdivi1处理的HDQ111细胞也表现出增加线粒体功能和突触活性，表明 Mdivi1 保护线粒体结构和功能，并提高细胞的存活率。当前的申请旨在确定 BACHD 转基因小鼠和 HD 敲入的神经元中 Drp1 是否部分减少小鼠线粒体分裂减少并降低 mHtt 诱导的毒性；以及是否 Mdivi1 BACHD 转基因小鼠和 HD 敲入小鼠的神经元中减少了过多的线粒体碎片化并增强线粒体功能和突触活性。这件事的结果研究将阐明遗传和药理学策略，这些策略可能会减少线粒体过度破碎并增加神经元存活和突触功能 HD 影响的神经元。