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：
9472711
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/9472711
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 Lipid Peroxides 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措施建立合理的基础策略以防止发作并减缓亨廷顿氏病的进展（高清）。越来越多的证据表明，突变体狩猎（MHTT）以及结构和功能线粒体异常参与HD中的神经元损伤和神经元丧失。几条证据支持线粒体异常参与HD 进展和发病机理：1）线粒体裂变的表达水平升高基因DRP1和FIS1在HD受影响的大脑区域的验尸组织中发现患者以及来自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的表达水平已在来自HD患者和BACHD转基因小鼠的这些相同影响的区域； 3）DRP1相互作用使用MHTT，这种相互作用随着HD的进展而增加。 4）GTPase DRP1的水平增加在高清神经元中发现了酶活性。 5）线粒体质量降低和运动性，线粒体的顺行轴突运输以及突触生存能力降低已经在来自Bachd转基因小鼠的原发性神经元中发现。一种治疗策略 HD可能涉及抑制线粒体碎片过多。几个线粒体裂变已经确定了抑制剂，包括线粒体分裂抑制剂MDIVI1。 mdivi1具有使用缺血/再灌注损伤模型，肾损伤和氧葡萄糖研究了剥夺。调查结果表明，MDIVI1降低了线粒体裂变并增加线粒体融合，并保持线粒体功能和细胞存活。在研究中 HD稳定纹状体细胞系中的线粒体动力学，带有111个PolyQ重复序列，研究人员发现，裂变基因的水平降低，融合基因的水平升高用MDIVI1处理的HDQ111细胞。 MDIVI1处理的HDQ111细胞也显示出增加线粒体功能和突触活动，表明MDIVI1保护线粒体结构和功能，并增强细胞存活。当前申请旨在确定 Bachd转基因小鼠和HD敲击素的神经元中DRP1的部分降低是否部分降低小鼠降低线粒体裂变并降低MHTT诱导的毒性。以及MDIVI1 在Bachd转基因小鼠和HD敲击蛋白小鼠的神经元中，线粒体过多碎片和增强线粒体功能和突触活动。结果的结果研究将是对遗传和药理策略的阐明，这些策略可能会减少线粒体碎片过多，并增加神经元存活和突触功能受hd影响的神经元。