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Abstract：
Huntington\'s disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the coding sequence of huntingtin protein. Initially, it predominantly affects medium-sized spiny neurons (MSSNs) of the corpus striatum. No effective treatment is still available, thus urging the identification of potential therapeutic targets. While evidence of mitochondrial structural alterations in HD exists, previous studies mainly employed 2D approaches and were performed outside the strictly native brain context. In this study, we adopted a novel multiscale approach to conduct a comprehensive 3D in situ structural analysis of mitochondrial disturbances in a mouse model of HD. We investigated MSSNs within brain tissue under optimal structural conditions utilizing state-of-the-art 3D imaging technologies, specifically FIB/SEM for the complete imaging of neuronal somas and Electron Tomography for detailed morphological examination, and image processing-based quantitative analysis. Our findings suggest a disruption of the mitochondrial network towards fragmentation in HD. The network of interlaced, slim and long mitochondria observed in healthy conditions transforms into isolated, swollen and short entities, with internal cristae disorganization, cavities and abnormally large matrix granules.
摘要：
亨廷顿病（HD）是一种遗传性神经退行性疾病，由亨廷顿蛋白编码序列中的CAG重复序列扩大引起。最初，它主要影响纹状体的中等大小的多刺神经元（MSSN）。仍然没有有效的治疗方法，从而敦促识别潜在的治疗靶点。虽然HD中存在线粒体结构改变的证据，以前的研究主要采用2D方法，并且在严格的自然大脑环境之外进行。在这项研究中,我们采用了一种新的多尺度方法对HD小鼠模型的线粒体紊乱进行了全面的3D原位结构分析。我们利用最先进的3D成像技术在最佳结构条件下研究了脑组织内的MSSN，特别是FIB/SEM，用于神经元躯体的完整成像和电子断层扫描，用于详细的形态学检查，和基于图像处理的定量分析。我们的发现表明，在HD中线粒体网络向碎片化的破坏。交错的网络，在健康条件下观察到的细长线粒体转化为孤立的，肿胀和短的实体，内部的cristae混乱，空腔和异常大的基质颗粒。
