Differential gene expression in the cortical sulcus compared to the gyral crest within the early stages of chronic traumatic encephalopathy.
Differential gene expression in the cortical sulcus compared to the gyral crest within the early stages of chronic traumatic encephalopathy.
复制标题
DOI：
10.17879/freeneuropathology-2021-3453
复制
发表时间：
2021-01-01
影响因子：
--
通讯作者：
Stein, Thor D
中科院分区：
文献类型：
--
作者：
Cherry, Jonathan D;Agus, Filisia;Stein, Thor D
慢性创伤性脑病（CTE）是一种进行性神经退行性脑病，常见于重复性头部撞击史（RHI）的个体。以往的研究表明，神经炎症参与了CTE的发病机制，但具体的炎症机制尚不清楚。在这里，我们使用rna测序和基因集富集分析（GSEA），研究了从CTE病理首次发现的区域皮质沟中提取的组织中发现的遗传变化，并将其与邻近的嵴组织进行比较，以确定与初始过度磷酸化tau （p-tau）沉积直接相关的途径。选取21例进行分析：6例未接触RHI或存在神经退行性疾病（对照组），5例接触RHI但未存在神经退行性疾病（RHI）， 10例接触RHI并伴有低期CTE （CTE）。鉴定出两组基因：在沟和嵴中都发生变化的基因和在沟相对于嵴中发生特异性变化的基因。当检查沟和嵴中改变的基因时，GSEA显示RHI组和CTE组免疫相关过程增加，神经元过程减少。观察到沟槽特异性改变由三种机制驱动：解剖学、RHI或p-tau。首先，我们观察到在所有组中，在免疫、细胞外基质、血管、神经元和内吞/胞外作用类别中都有一致的沟特异性改变，这表明与相邻的嵴相比，沟具有独特的分子特征，独立于病理。其次，有RHI病史的个体表现出代谢和线粒体相关过程的损伤。最后，在CTE患者中，我们观察到免疫和吞噬相关过程的损伤。总的来说，这项工作提供了第一次观察到在沟中特异性改变的生物过程，这可能直接涉及CTE的发病机制，并为生物标志物和治疗提供了新的靶点。
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative tauopathy found in individuals with a history of repetitive head impacts (RHI). Previous work has demonstrated that neuroinflammation is involved in CTE pathogenesis, however, the specific inflammatory mechanisms are still unclear. Here, using RNA-sequencing and gene set enrichment analysis (GSEA), we investigated the genetic changes found in tissue taken from the region CTE pathology is first found, the cortical sulcus, and compared it to neighboring gryal crest tissue to identify what pathways were directly related to initial hyperphosphorylated tau (p-tau) deposition. 21 cases were chosen for analysis: 6 cases had no exposure to RHI or presence of neurodegenerative disease (Control), 5 cases had exposure to RHI but no presence of neurodegenerative disease (RHI), and 10 cases had exposure to RHI and low stage CTE (CTE). Two sets of genes were identified: genes that changed in both the sulcus and crest and genes that changed specifically in the sulcus relative to the crest. When examining genes that changed in both the sulcus and crest, GSEA demonstrated an increase in immune related processes and a decrease in neuronal processes in RHI and CTE groups. Sulcal specific alterations were observed to be driven by three mechanisms: anatomy, RHI, or p-tau. First, we observed consistent sulcal specific alterations in immune, extracellular matrix, vascular, neuronal, and endocytosis/exocytosis categories across all groups, suggesting the sulcus has a unique molecular signature compared to the neighboring crest independent of pathology. Second, individuals with a history of RHI demonstrated impairment in metabolic and mitochondrial related processes. Finally, in individuals with CTE, we observed impairment of immune and phagocytic related processes. Overall, this work provides the first observation of biological processes specifically altered in the sulcus that could be directly implicated in CTE pathogenesis and provide novel targets for biomarkers and therapies.