Unique nigral and cortical pathways implicated by epigenomic and transcriptional analyses in a rotenone rat model of Parkinson’s disease [RNA-Seq]

Pesticide exposure is increasingly recognised as a potential environmental factor contributing to the onset of idiopathic Parkinson’s disease, yet the molecular mechanisms underlying this connection remain unclear. This study aims to explore how pesticide exposure disrupts key brain regions involved in Parkinson’s disease pathology by reshaping gene expression and epigenetic landscapes. Using the well established rotenone rat model of the disease, we used H3K27ac ChIP-sequencing and RNA-sequencing to profile active regulatory elements and transcriptional activity in the substantia nigra and cortex. We identified widespread transcriptomic and epigenetic differences which are consistent across the assays. Our results indicate there is a strong immune response to rotenone localised to the substantia nigra and highlight an enrichment of immune-related motifs in this brain region, suggesting that the immune response is at least partially driven by gene regulatory mechanisms. We also noted an increase in C1q complement pathway activity in the substantia nigra. In contrast, we identified widespread dysregulation of synaptic function at the gene regulatory level in the cortex of these same rats. Our results highlight a role for gene regulatory mechanisms potentially mediating the effects of pesticide exposure, driving region-specific functional responses in the brain that may contribute to the pathology of Parkinson’s disease.农药暴露日益被认为是诱发特发性帕金森病（idiopathic Parkinson’s disease）的潜在环境因素之一，然而二者关联背后的分子机制仍未明确。本研究旨在探究农药暴露如何通过重塑基因表达与表观遗传景观，破坏帕金森病病理进程中关键脑区的正常功能。本研究采用已成熟的鱼藤酮（rotenone）帕金森病大鼠模型，借助H3K27ac染色质免疫共沉淀测序（ChIP-sequencing）与RNA测序（RNA-sequencing），对黑质（substantia nigra）与大脑皮层（cortex）中的活性调控元件及转录活性开展谱学表征。本研究在两类测序实验中均检测到广泛存在的转录组与表观遗传组差异，且结果具有一致性。研究结果显示，黑质区域对鱼藤酮存在强烈的免疫应答，且该脑区中免疫相关基序显著富集，提示此类免疫应答至少部分由基因调控机制所介导。此外，我们还观察到黑质区域内C1q补体通路的活性上调。与之形成对比的是，在同一批大鼠的大脑皮层中，我们发现基因调控层面存在广泛的突触功能失调现象。本研究结果凸显了基因调控机制在介导农药暴露影响中的潜在作用：此类机制可驱动脑区特异性的功能应答，进而可能参与帕金森病的病理进程。