Characterizing the molecular and pathological alterations of the sulcus versus crest in early and late stages of chronic traumatic encephalopathy
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Abstract
Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy characterized by the perivascular deposition of hyperphosphorylated tau (p-tau) in neurons and glia at the depths of the cortical sulci in an irregular spatial pattern. Exposure to repetitive head impacts (RHI), which are commonly sustained through contact sports and military service. CTE can only be diagnosed post-mortem, so a better understanding of the molecular alterations that are occurring may lead to discovery of novel biomarkers and contribute to advancements in therapeutic development. Even though the sulcus and crest are only millimeters away, there seems to be unique biological processes in each region. Previous work from our laboratory has looked at the sulcus versus crest in Low CTE, RHI and control. Here, we are building on results from that study, using RNA-sequencing and gene set enrichment analysis (GSEA), to also compare the sulcus versus crest in Low CTE and High CTE. 15 cases were chosen for analysis: 7 Low CTE and 8 High CTE. Genes and biological processes that changed specifically in the sulcus compared to the crest were identified. First, we observed that 50% of the biological processes from GSEA had an opposite direction of effect when Low CTE was compared to High CTE. Second, there were more upregulated biological processes in the sulcus in mild disease compared to severe disease: immune, signaling, extracellular matrix, neuronal, mitochondrial, protein processing, and cell cycle. This suggests unique biological processes occurring in the sulcus and crest of each disease state. Finally, two genes, DOK3 and CAV1, were selected for histologic validation and analyzation, and to explore possible mechanistic connects to disease progression. Overall, this work provides the first comparison of the crest versus sulcus in Low CTE compared to High CTE, allowing us to better understand how the molecular mechanisms are altered through disease pathogenesis and provide novel biomarkers and targets for therapeutics.