Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Advanced Microscopy Laboratory, University of Zaragoza, Zaragoza, Spain.
Acta Neuropathol Commun. 2024 Jun 5;12(1):88. doi: 10.1186/s40478-024-01802-2.
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.
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 CAG 重复扩展引起。最初，它主要影响纹状体的中型棘突神经元（MSSNs）。目前仍然没有有效的治疗方法，因此迫切需要确定潜在的治疗靶点。虽然有证据表明 HD 存在线粒体结构改变，但以前的研究主要采用二维方法，并且是在严格的天然脑环境之外进行的。在这项研究中，我们采用了一种新的多尺度方法，对 HD 小鼠模型中线粒体紊乱进行全面的 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脑组织中的 MSSNs，具体来说，FIB/SEM 用于完整成像神经元胞体，电子断层扫描用于详细的形态学检查，以及基于图像处理的定量分析。我们的研究结果表明，HD 中线粒体网络出现碎片化破坏。在健康状态下观察到的交织、细长的线粒体网络转变为孤立、肿胀和短的线粒体，内部嵴结构紊乱、出现空腔和异常大的基质颗粒。
