Histone Acetylation Contributes to Mitochondrial Dysfunction and Neuroinflammation in Parkinson's disease

Parkinson's disease (PD) is pathologically recognized by the irreversible, progressive loss of dopaminergic (DAergic) neurons in the SNpc and aberrant deposition of protein misfolding (α-synuclein aggregation) in Lewy neurites and Lewy bodies. Aberrant epigenetic modification has been implicated in the pathogenesis of PD. By using environmental neurotoxicants rotenone, pyridaben, paraquat, and manganese as research tools, this dissertation looks at the molecular and cellular mechanism and hypotheses in PD pathogenesis from the perspective of histone dysregulation (including acetylation and methylation). Mitochondrial dysfunction is a major pathophysiological contributor to PD progression. However, the mechanistic landscape of histone dysregulation in mitochondrial dysfunction-driven PD has yet to be fully explored. Upon this scenario, Chapter 2-4 focus on studying mitochondrial dysfunction-driven neuronal degeneration. We first characterized acetylation sites of core histone H3 and then looked at histone H4 with DAergic neuronal cell cultures, ex vivo nigral brain slice culture, in vivo mouse models MitoParks, and postmortem human PD brains. We also integrated bioinformatics analysis of ChIP-Seq and RNA-Seq on mitochondria-impaired DAergic neuronal models to identify vulnerable epigenomic loci regulated by H3K27 hyperacetylation in both environment- and mitochondrial genetic mutation-linked DAergic neurodegeneration. The crosstalk between proteasome impairment and mitochondrial dysfunction and tilted HAT/HDAC balance (including H3K27ac, HDAC isoforms, and p300) were studied to dissect more layers of the complex mechanism attributed to the cause of PD. Environmental risk factors can induce microglia to release an excess of inflammatory cytokines, generating exaggerated neuroinflammation and consequently impacting the progression of PD in later life. Chapter 5 turns to investigate persistent microglial neuroinflammation. Epigenetic reprogramming is the ability of innate immune cells to form memories of environmental stimuli (priming), allowing for heightened responses to secondary stressors. Environmental manganese (Mn) exposure has been linked to Parkinsonism in humans. To this, we explored microglial epigenetic imprinting using LPS as a memory priming trigger and Mn as the secondary environmental trigger. We explored the landscape of aberrant acetylation or methylation on core histone H3 and H4 and their subsequent transcription alteration in the context of mitochondrial dysfunction or persistent neuroinflammation to uncover the molecular mechanism underlying PD.