Petrasch-Parwez Elisabeth, Nguyen Huu-Phuc, Löbbecke-Schumacher Marlen, Habbes Hans-Werner, Wieczorek Stefan, Riess Olaf, Andres Karl-Hermann, Dermietzel Rolf, Von Hörsten Stephan
Department of Neuroanatomy and Molecular Brain Research, Ruhr-University Bochum, 44801 Bochum, Germany.
J Comp Neurol. 2007 Apr 10;501(5):716-30. doi: 10.1002/cne.21272.
Huntington disease (HD) is a progressive neurodegenerative disorder characterized by emotional, cognitive, and motor dysfunctions. Aggregation of huntingtin is a hallmark of HD and, therefore, a crucial parameter for the evaluation of HD animal models. We investigated here the regional, cellular, and subcellular distribution of N-terminal huntingtin aggregates and associated neuropathological changes in the forebrain of a rat transgenic for HD (tgHD). The tgHD rat brain showed enormously enlarged lateral ventricles and a similar atrophy of cortical and subcortical areas as known in HD patients. Huntingtin aggregates of varying size and forms were regionally identified in neuronal nuclei, cytoplasm, dendrites, dendritic spines, axons, and synaptic terminals, closely resembling the results described earlier for human HD brains and in established HD mouse models. Huntingtin aggregates in mitochondria support mitochondrial dysfunction as contributing to the disease pathogenesis. Dark cell degeneration was reminiscent of results in HD individuals and HD mouse models. Interestingly, huntingtin aggregates were especially well accumulated in two interacting limbic forebrain systems, the ventral striatopallidum and the extended amygdala, which may contribute to the early onset of emotional changes observed in the tgHD rat. In conclusion, the tgHD rat model reflects to a remarkable extent the cellular and subcellular neuropathological key features as observed in human HD and HD mouse brains and hints of changes in limbic forebrain systems, which may elucidate the emotional dysfunction in the tgHD rat and affective disturbances in HD patients.
亨廷顿舞蹈症（HD）是一种进行性神经退行性疾病，其特征为情绪、认知和运动功能障碍。亨廷顿蛋白的聚集是HD的一个标志，因此也是评估HD动物模型的一个关键参数。我们在此研究了HD转基因大鼠（tgHD）前脑中N端亨廷顿蛋白聚集体的区域、细胞和亚细胞分布以及相关的神经病理学变化。tgHD大鼠脑显示侧脑室大幅扩大，皮质和皮质下区域出现与HD患者类似的萎缩。在神经元细胞核、细胞质、树突、树突棘、轴突和突触终末中可区域化识别出大小和形态各异的亨廷顿蛋白聚集体，这与先前针对人类HD脑和已建立的HD小鼠模型所描述的结果极为相似。线粒体中的亨廷顿蛋白聚集体支持线粒体功能障碍，这是疾病发病机制的一个因素。暗细胞变性让人联想到HD个体和HD小鼠模型中的结果。有趣的是，亨廷顿蛋白聚集体尤其大量积聚在两个相互作用的边缘前脑系统，即腹侧纹状体苍白球和扩展杏仁核中，这可能导致了在tgHD大鼠中观察到的情绪变化的早期发作。总之，tgHD大鼠模型在很大程度上反映了在人类HD和HD小鼠脑中观察到的细胞和亚细胞神经病理学关键特征以及边缘前脑系统的变化迹象，这可能阐明了tgHD大鼠的情绪功能障碍和HD患者的情感障碍。
