Mitochondrial Fragmentation and Neurodegeneration in Huntington's Disease

我们研究的长期目标是建立一个合理的基础， 预防和减缓亨廷顿病进展的策略 （HD）.越来越多的证据表明，突变亨廷顿蛋白（mHtt）和结构和功能 线粒体的异常涉及HD中的神经元损伤和神经元损失。 几条证据支持线粒体异常参与HD 进展和发病机制：1）线粒体分裂的表达水平增加 基因Drp 1和Fis 1已在HD患者受影响脑区的死后组织中发现， 在BACHD转基因小鼠的纹状体和皮质组织中; 2）减少 线粒体融合基因Mfn 1、Mfn 2和Opa 1的表达水平已在 来自HD患者和BACHD转基因小鼠的这些相同的受影响区域; 3）Drp 1相互作用 与mHtt，这种相互作用随着HD进展而增加; 4）GTdR Drp 1水平增加 已在HD神经元中发现酶活性;和5）线粒体质量减少， 运动性、线粒体的顺行轴突运输减少和突触活力降低 在BACHD转基因小鼠的原代神经元中发现。的治疗策略 HD可能涉及抑制过度的线粒体片段化。几个线粒体分裂 已经鉴定了抑制剂，包括线粒体分裂抑制剂Mdivi 1。Mdivi 1有 使用缺血/再灌注损伤模型、肾损伤和氧-葡萄糖 剥夺研究结果表明，Mdivi 1减少线粒体分裂， 线粒体融合，并维持线粒体功能和细胞存活。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， HDQ 111细胞用Mdivil处理。Mdivi 1处理的HDQ 111细胞也显示出增加的 线粒体功能和突触活动，表明Mdivi 1保护线粒体功能， 结构和功能，并增强细胞存活。本申请旨在确定 BACHD转基因小鼠神经元中Drp 1的部分减少和HD敲入除是否 小鼠减少线粒体分裂并降低mHtt诱导的毒性;以及Mdivi 1 在来自BACHD转基因小鼠和HD敲入小鼠的神经元中， 分裂和增强线粒体功能和突触活动。这场 研究将阐明遗传和药理学策略， 过度的线粒体碎片和增加神经元的存活和突触功能， HD影响的神经元。

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.