Inflammation and neuronal gene expression changes differ in early versus late chronic traumatic encephalopathy brain.
Inflammation and neuronal gene expression changes differ in early versus late chronic traumatic encephalopathy brain.
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DOI：
10.1186/s12920-023-01471-5
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发表时间：
2023-03-09
影响因子：
2.7
通讯作者：
中科院分区：
文献类型：
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作者：
我们对慢性创伤性脑病（CTE）的分子基础及其在死后大脑中的相关病理学的理解是不完整的。包括游戏年限和遗传风险变异在内的因素会影响与疾病表达相关的tau病理学程度，但这些因素如何影响基因表达，以及这些影响在疾病发展过程中是否一致，目前尚不清楚。为了解决这些问题，我们对迄今为止最大的死后脑CTE mRNASeq全转录组数据集进行了分析。我们通过比较CTE患者与缺乏CTE病理学的重复头部撞击史的对照组患者，研究了与疾病相关的基因和生物学过程。然后，我们确定了与总游戏年数相关的基因和生物学过程，作为暴露的衡量标准，死亡时存在的tau病理量以及APOE和TMEM 106 B风险变体的存在。根据McKee CTE分期标准将样本分为低病理组和高病理组，以模拟暴露后的早期与晚期变化，并比较这些组之间与这些因素相关的相对影响。对于大多数这些因素，大量基因表达变化与严重疾病相关，主要涉及多种强烈参与的神经炎症和神经免疫过程。相比之下，低病理组涉及的基因和过程少得多，并且与严重疾病相比，在某些因素上显示出显着差异。具体而言，当在这两组之间进行比较时，与tau病理学量相关的基因表达显示出几乎完美的反比关系。总之，这些结果表明，早期CTE疾病过程可能与晚期发生的情况在机制上不同，总的发病年数和tau病理学对疾病表达的影响不同，并且相关的病理学修饰风险变体可能通过不同的生物学途径这样做。 在线版本包含补充材料，可通过10.1186/s12920-023-01471-5获得。
Our understanding of the molecular underpinnings of chronic traumatic encephalopathy (CTE) and its associated pathology in post-mortem brain is incomplete. Factors including years of play and genetic risk variants influence the extent of tau pathology associated with disease expression, but how these factors affect gene expression, and whether those effects are consistent across the development of disease, is unknown. To address these questions, we conducted an analysis of the largest post-mortem brain CTE mRNASeq whole-transcriptome dataset available to date. We examined the genes and biological processes associated with disease by comparing individuals with CTE with control individuals with a history of repetitive head impacts that lack CTE pathology. We then identified genes and biological processes associated with total years of play as a measure of exposure, amount of tau pathology present at time of death, and the presence of APOE and TMEM106B risk variants. Samples were stratified into low and high pathology groups based on McKee CTE staging criteria to model early versus late changes in response to exposure, and the relative effects associated with these factors were compared between these groups. Substantial gene expression changes were associated with severe disease for most of these factors, primarily implicating diverse, strongly involved neuroinflammatory and neuroimmune processes. In contrast, low pathology groups had many fewer genes and processes implicated and show striking differences for some factors when compared with severe disease. Specifically, gene expression associated with amount of tau pathology showed a nearly perfect inverse relationship when compared between these two groups. Together, these results suggest the early CTE disease process may be mechanistically different than what occurs in late stages, that total years of play and tau pathology influence disease expression differently, and that related pathology-modifying risk variants may do so via distinct biological pathways. The online version contains supplementary material available at 10.1186/s12920-023-01471-5.
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影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
14.9
作者：
The Gene Ontology Consortium
通讯作者：
The Gene Ontology Consortium
影响因子：
--
作者：
Cherry, Jonathan D;Agus, Filisia;Stein, Thor D
通讯作者：
Stein, Thor D
影响因子：
29
作者：
通讯作者：
--
DOI：
10.1097/nen.0000000000000151
发表时间：
2015-01-01
影响因子：
3.2
作者：
Nelson, Peter T.;Wang, Wang-Xia;Fardo, David W.
通讯作者：
Fardo, David W.