Background The earliest white matter changes in Huntington’s disease are seen before disease onset in the premanifest stage around the striatum, within the corpus callosum, and in posterior white matter tracts. While experimental evidence suggests that these changes may be related to abnormal gene transcription, we lack an understanding of the biological processes driving this regional vulnerability. Methods Here, we investigate the relationship between regional transcription in the healthy brain, using the Allen Institute for Brain Science transcriptome atlas, and regional white matter connectivity loss at three time points over 24 months in subjects with premanifest Huntington’s disease relative to control participants. The baseline cohort included 72 premanifest Huntington’s disease participants and 85 healthy control participants. Results We show that loss of corticostriatal, interhemispheric, and intrahemispheric white matter connections at baseline and over 24 months in premanifest Huntington’s disease is associated with gene expression profiles enriched for synaptic genes and metabolic genes. Corticostriatal gene expression profiles are predominately associated with motor, parietal, and occipital regions, while interhemispheric expression profiles are associated with frontotemporal regions. We also show that genes with known abnormal transcription in human Huntington’s disease and animal models are overrepresented in synaptic gene expression profiles, but not in metabolic gene expression profiles. Conclusions These findings suggest a dual mechanism of white matter vulnerability in Huntington’s disease, in which abnormal transcription of synaptic genes and metabolic disturbance not related to transcription may drive white matter loss.

中文翻译：

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亨廷顿病中显示白质丢失的大脑区域富含突触和代谢基因


背景 亨廷顿病中最早的白质变化出现在疾病发作前的纹状体周围、胼胝体内和后白质束中的前期阶段。虽然实验证据表明这些变化可能与异常基因转录有关，但我们对驱动这种区域脆弱性的生物过程缺乏了解。方法在这里，我们使用艾伦脑科学研究所转录组图谱研究了患有前期亨廷顿病的受试者相对于对照参与者在 24 个月内三个时间点的健康大脑中的区域转录与区域白质连接丧失之间的关系。基线队列包括 72 名患有亨廷顿病的参与者和 85 名健康对照参与者。结果我们发现，在亨廷顿舞蹈病发作前的24个月内，皮质纹状体、半球间和半球内白质连接的丧失与突触基因和代谢基因丰富的基因表达谱相关。皮质纹状体基因表达谱主要与运动区、顶叶区和枕叶区相关，而半球间表达谱与额颞叶区相关。我们还表明，在人类亨廷顿病和动物模型中已知转录异常的基因在突触基因表达谱中过多，但在代谢基因表达谱中则不然。结论这些发现表明亨廷顿病白质脆弱性的双重机制，其中突触基因的异常转录和与转录无关的代谢紊乱可能导致白质损失。