Neurogenetics Laboratory, Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
Hum Mol Genet. 2012 Jan 15;21(2):406-20. doi: 10.1093/hmg/ddr475. Epub 2011 Oct 13.
The purpose of this study was to investigate the link between mutant huntingtin (Htt) and neuronal damage in relation to mitochondria in Huntington's disease (HD). In an earlier study, we determined the relationship between mutant Htt and mitochondrial dynamics/synaptic viability in HD patients. We found mitochondrial loss, abnormal mitochondrial dynamics and mutant Htt association with mitochondria in HD patients. In the current study, we sought to expand on our previous findings and further elucidate the relationship between mutant Htt and mitochondrial and synaptic deficiencies. We hypothesized that mutant Htt, in association with mitochondria, alters mitochondrial dynamics, leading to mitochondrial fragmentation and defective axonal transport of mitochondria in HD neurons. In this study, using postmortem HD brains and primary neurons from transgenic BACHD mice, we identified mutant Htt interaction with the mitochondrial protein Drp1 and factors that cause abnormal mitochondrial dynamics, including GTPase Drp1 enzymatic activity. Further, using primary neurons from BACHD mice, for the first time, we studied axonal transport of mitochondria and synaptic degeneration. We also investigated the effect of mutant Htt aggregates and oligomers in synaptic and mitochondrial deficiencies in postmortem HD brains and primary neurons from BACHD mice. We found that mutant Htt interacts with Drp1, elevates GTPase Drp1 enzymatic activity, increases abnormal mitochondrial dynamics and results in defective anterograde mitochondrial movement and synaptic deficiencies. These observations support our hypothesis and provide data that can be utilized to develop therapeutic targets that are capable of inhibiting mutant Htt interaction with Drp1, decreasing mitochondrial fragmentation, enhancing axonal transport of mitochondria and protecting synapses from toxic insults caused by mutant Htt.
本研究旨在探讨亨廷顿病（HD）中突变 huntingtin（Htt）与神经元损伤和线粒体之间的关系。在早期研究中，我们确定了突变 Htt 与 HD 患者中线粒体动力学/突触活力之间的关系。我们发现线粒体丧失、线粒体动力学异常以及突变 Htt 与线粒体在 HD 患者中的关联。在当前的研究中，我们试图扩展我们之前的发现，并进一步阐明突变 Htt 与线粒体和突触缺陷之间的关系。我们假设，与线粒体结合的突变 Htt 会改变线粒体动力学，导致线粒体碎片化和 HD 神经元中线粒体的轴突运输缺陷。在这项研究中，我们使用了死后 HD 大脑和转基因 BACHD 小鼠的原代神经元，鉴定了突变 Htt 与线粒体蛋白 Drp1 的相互作用，以及导致异常线粒体动力学的因素，包括 GTPase Drp1 酶活性。此外，我们首次使用 BACHD 小鼠的原代神经元研究了线粒体的轴突运输和突触退化。我们还研究了突变 Htt 聚集体和低聚物对死后 HD 大脑和 BACHD 小鼠原代神经元中突触和线粒体缺陷的影响。我们发现突变 Htt 与 Drp1 相互作用，提高 GTPase Drp1 酶活性，增加异常线粒体动力学，并导致顺行性线粒体运动和突触缺陷。这些观察结果支持我们的假设，并提供了可用于开发治疗靶点的数据，这些靶点能够抑制突变 Htt 与 Drp1 的相互作用，减少线粒体碎片化，增强线粒体的轴突运输，并保护突触免受突变 Htt 引起的毒性损伤。
