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

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE280520 | GEO | 2025/06/18

REPOSITORIES: GEO

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

Project description: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.

2025-06-18 | GSE280519 | GEO

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Project description:Strong evidence in human populations indicates that pesticide exposure increases the risk of Parkinson's disease . However, to date there has no study investigating the role of genetic pathways for pesticide induced PD at cellular resolution. We used single cell RNA sequencing to provide fine-grained information on the genetic pathways of Parkinson's disease caused by a combined regimen of maneb and paraquat. We investigated the substantia nigra pars compacta of control mice and mice treated with maneb and paraquat to identify changes in gene expression in cellular subpopulations such as neurons, glia and vascular cells. This work reveals how neuronal and non-neuronal cells interact in the context of a toxicologically and environmentally relevant model Parkinson's disease, while offering entry points to the design of new therapies.

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