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Early white matter pathology in the fornix of the limbic system in Huntington disease
Acta Neuropathologica ( IF 12.7 ) Pub Date : 2021-08-26 , DOI: 10.1007/s00401-021-02362-8
Sanaz Gabery 1 , Jing Eugene Kwa 2 , Rachel Y Cheong 1 , Barbara Baldo 1, 3 , Costanza Ferrari Bardile 2, 4 , Brendan Tan 5 , Catriona McLean 6 , Nellie Georgiou-Karistianis 5 , Govinda R Poudel 5 , Glenda Halliday 7 , Mahmoud A Pouladi 2, 4, 8 , Åsa Petersén 1
Affiliation  

Huntington disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. The typical motor symptoms have been associated with basal ganglia pathology. However, psychiatric and cognitive symptoms often precede the motor component and may be due to changes in the limbic system. Recent work has indicated pathology in the hypothalamus in HD but other parts of the limbic system have not been extensively studied. Emerging evidence suggests that changes in HD also include white matter pathology. Here we investigated if the main white matter tract of the limbic system, the fornix, is affected in HD. We demonstrate that the fornix is 34% smaller already in prodromal HD and 41% smaller in manifest HD compared to controls using volumetric analyses of MRI of the IMAGE-HD study. In post-mortem fornix tissue from HD cases, we confirm the smaller fornix volume in HD which is accompanied by signs of myelin breakdown and reduced levels of the transcription factor myelin regulating factor but detect no loss of oligodendrocytes. Further analyses using RNA-sequencing demonstrate downregulation of oligodendrocyte identity markers in the fornix of HD cases. Analysis of differentially expressed genes based on transcription-factor/target-gene interactions also revealed enrichment for binding sites of SUZ12 and EZH2, components of the Polycomb Repressive Complex 2, as well as RE1 Regulation Transcription Factor. Taken together, our data show that there is early white matter pathology of the fornix in the limbic system in HD likely due to a combination of reduction in oligodendrocyte genes and myelin break down.



中文翻译:

亨廷顿病边缘系统穹窿的早期白质病理学

亨廷顿病 (HD) 是一种致命的神经退行性疾病,由亨廷顿 ( HTT ) 中 CAG 重复序列的扩大引起) 基因。典型的运动症状与基底节病变有关。然而,精神和认知症状通常先于运动成分,并且可能是由于边缘系统的变化。最近的工作表明 HD 下丘脑的病理学,但边缘系统的其他部分尚未得到广泛研究。新出现的证据表明,HD 的变化还包括白质病理学。在这里,我们调查了边缘系统的主要白质束,穹窿是否在 HD 中受到影响。我们证明,与使用 IMAGE-HD 研究的 MRI 体积分析的对照相比,前驱 HD 中的穹窿已经小了 34%,而明显的 HD 中的穹窿小了 41%。在 HD 病例的死后穹窿组织中,我们证实了 HD 中较小的穹窿体积伴随着髓鞘分解的迹象和转录因子髓鞘调节因子水平的降低,但未检测到少突胶质细胞的损失。使用 RNA 测序的进一步分析表明 HD 病例穹窿中少突胶质细胞识别标记的下调。基于转录因子/靶基因相互作用的差异表达基因分析还揭示了 SUZ12 和 EZH2、Polycomb 抑制复合物 2 的组分以及 RE1 调节转录因子的结合位点的富集。综上所述,我们的数据表明,HD 患者边缘系统穹窿的早期白质病理学可能是由于少突胶质细胞基因减少和髓磷脂分解的共同作用。

更新日期:2021-08-27
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