Unique nigral and cortical pathways implicated by epigenomic and transcriptional analyses in a rotenone rat model of Parkinson’s disease
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Type
Journal Article
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 regulatory landscapes.
Using the well-established rotenone rat model of the disease, we performed H3K27ac ChIP sequencing to profile active regulatory elements in the substantia nigra and motor cortex. In this
model, rotenone distributes uniformly throughout the brain, and the degree of complex I inhibition
is equivalent in cortical and substantia nigra neurons. Despite the uniformity of complex I
inhibition, we identified widespread epigenomic differences, with brain region specific acetylation
patterns associated with rotenone exposure. We showed consistent changes in transcriptomic
activity by RNA-sequencing. Our results indicate there is a strong immune response caused by
rotenone localised to the substantia nigra that highlights an enrichment of immune-related motifs.
This suggests rotenone-induced 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 and selective vulnerability
that characterise Parkinson’s disease.
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 regulatory landscapes.
Using the well-established rotenone rat model of the disease, we performed H3K27ac ChIP sequencing to profile active regulatory elements in the substantia nigra and motor cortex. In this
model, rotenone distributes uniformly throughout the brain, and the degree of complex I inhibition
is equivalent in cortical and substantia nigra neurons. Despite the uniformity of complex I
inhibition, we identified widespread epigenomic differences, with brain region specific acetylation
patterns associated with rotenone exposure. We showed consistent changes in transcriptomic
activity by RNA-sequencing. Our results indicate there is a strong immune response caused by
rotenone localised to the substantia nigra that highlights an enrichment of immune-related motifs.
This suggests rotenone-induced 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 and selective vulnerability
that characterise Parkinson’s disease.
Date Issued
2025-07-24
Date Acceptance
2025-06-11
Citation
npj Parkinson's Disease, 2025, 11
ISSN
2373-8057
Publisher
Nature Portfolio
Journal / Book Title
npj Parkinson's Disease
Volume
11
Copyright Statement
Copyright This paper is embargoed until publication. Once published the Version of Record (VoR) will be available on immediate open access.
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Publication Status
Published
Article Number
ARTN 217