Brain Regions Showing White Matter Loss in Huntington's Disease Are Enriched for Synaptic and Metabolic Genes.
Brain Regions Showing White Matter Loss in Huntington's Disease Are Enriched for Synaptic and Metabolic Genes.
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DOI：
10.1016/j.biopsych.2017.10.019
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发表时间：
2018-03-01
影响因子：
10.6
通讯作者：
Track-On HD Investigators
中科院分区：
文献类型：
--
作者：
McColgan P;Gregory S;Seunarine KK;Razi A;Papoutsi M;Johnson E;Durr A;Roos RAC;Leavitt BR;Holmans P;Scahill RI;Clark CA;Rees G;Tabrizi SJ;Track-On HD Investigators
亨廷顿氏病最早的白色物质变化见于疾病发作前的表现前期，纹状体周围、胼胝体内和后部白色物质束。虽然实验证据表明，这些变化可能与异常的基因转录有关，但我们对驱动这种区域脆弱性的生物过程缺乏了解。在这里，我们调查区域转录在健康的大脑之间的关系，使用艾伦研究所脑科学转录组图谱，区域白色物质连接损失在三个时间点超过24个月的受试者与前显亨廷顿氏病相对于控制参与者。基线队列包括72名预显亨廷顿病参与者和85名健康对照参与者。我们发现，在基线和超过24个月的表现前亨廷顿病中，皮质纹状体、半球间和半球内白色物质连接的丧失与突触基因和代谢基因的基因表达谱富集有关。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区相关。我们还表明，在人类亨廷顿舞蹈病和动物模型中，已知异常转录的基因在突触基因表达谱中过度表达，但在代谢基因表达谱中则不然。这些发现表明亨廷顿舞蹈病中白色物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驱动白色物质损失。
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. 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. 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. 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.
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影响因子：
25
作者：
Langfelder P;Cantle JP;Chatzopoulou D;Wang N;Gao F;Al-Ramahi I;Lu XH;Ramos EM;El-Zein K;Zhao Y;Deverasetty S;Tebbe A;Schaab C;Lavery DJ;Howland D;Kwak S;Botas J;Aaronson JS;Rosinski J;Coppola G;Horvath S;Yang XW
通讯作者：
Yang XW
影响因子：
4.8
作者：
Jeurissen, Ben;Leemans, Alexander;Sijbers, Jan
通讯作者：
Sijbers, Jan
影响因子：
3.4
作者：
Fusco, FR;Zuccato, C;Bernardi, G
通讯作者：
Bernardi, G
影响因子：
25
作者：
Ramasamy, Adaikalavan;Trabzuni, Daniah;Guelfi, Sebastian;Varghese, Vibin;Smith, Colin;Walker, Robert;De, Tisham;Coin, Lachlan;de Silva, Rohan;Cookson, Mark R.;Singleton, Andrew B.;Hardy, John;Ryten, Mina;Weale, Michael E.
通讯作者：
Weale, Michael E.
影响因子：
3.7
作者：
Di Paola, M.;Luders, E.;Sabatini, U.
通讯作者：
Sabatini, U.