Mitochondrial Fragmentation and Neurodegeneration in Huntington's Disease

我们研究的长期目标是开发神经保护的合理基础 预防和减缓亨廷顿病发病和进展的策略 (HD)。越来越多的证据表明，突变的亨廷顿蛋白(MHTT)及其结构和功能 线粒体异常参与了HD的神经元损伤和神经元丢失。 多条证据支持线粒体异常参与HD 进展与发病机制：1)线粒体分裂表达水平升高 在HD患者受累脑区的死后组织中发现了Drp1和Fis1基因 患者和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Mfn1、Mfn2和OPA1的表达水平已在 来自HD患者和BACHD转基因小鼠的相同的受影响区域；3)Drp1相互作用 对于mHTT，这种相互作用随着HD的进展而增加；4)GTP酶Drp1水平增加 在HD神经元中发现了酶活性；以及5)线粒体质量和 运动性，线粒体顺行轴突运输减少，突触活性降低 已在BACHD转基因小鼠的原代神经元中发现。一种治疗策略 HD可能涉及抑制过度的线粒体碎裂。几个线粒体的分裂 已经确定了抑制物，包括线粒体分裂抑制物MDi1。MDivi1有 已使用缺血/再灌注损伤模型、肾脏损伤和氧-葡萄糖进行研究 剥夺。研究结果表明，MDi1减少了线粒体的分裂并增加了 线粒体融合，维持线粒体功能和细胞存活。在…的研究中 携带111个多聚Q重复序列的HD稳定纹状体细胞系的线粒体动力学， 研究人员发现，核裂变基因水平降低，融合基因水平上升 HDQ111细胞经MDi1处理后，细胞周期延长。MDi1处理的HDQ111细胞也显示出增加 线粒体功能和突触活性，提示MDi1对线粒体有保护作用 结构和功能，并提高细胞存活率。当前应用程序试图确定 BACHD转基因小鼠神经元中Drp1的部分减少与HD敲打 小鼠减少线粒体分裂，减少mHTT诱导的毒性； 在BACHD转基因小鼠和HD敲击小鼠的神经元中减少多余的线粒体 碎裂并增强线粒体功能和突触活性。这样做的结果是 研究将阐明基因和药物策略可能会降低 线粒体过度碎裂增加神经元存活率和突触功能 受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.