Genetic and epigenetic complexity of Parkinson's disease: From dopamine pathways to estrogen interplay

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by selective loss of nigrostriatal dopaminergic neurons and extensive circuit disruption, clinically presenting with motor deficits and many non-motor symptoms. Pathologically, PD is linked to the aggregation of α-synuclein, mitochondrial and lysosomal stress, and chronic neuroinflammation. This chapter integrates the genetic and epigenetic framework of Parkinson's disease, encompassing rare monogenic factors such as SNCA, LRRK2, GBA1, PINK1, and PRKN that converge on proteostasis disruption, compromised mitophagy, and lysosomal dysfunction, alongside polygenic susceptibility that may be exacerbated by environmental influences. Epigenetic dysregulation further influences susceptibility and disease progression: altered DNA methylation and hydroxymethylation at PD-relevant loci such as PARK7 and NR4A2, maladaptive histone regulation (including increased HDAC2/3 activity), and non-coding RNA networks (miR-7, HOTAIR, circSNCA) that modulate α-synuclein expression, inflammatory pathways, mitochondrial dynamics, and clearance mechanisms. Sex dimorphism is emphasized as a biologically significant modifier, with males exhibiting a higher incidence and accelerated progression in numerous cohorts, whereas estrogen-associated signaling may provide neuroprotection through increased dopamine biosynthesis, enhanced antioxidant capacity, and inhibition of microglial activation-effects that may diminish post-menopause. This chapter integrates recent advancements by linking mechanistic insights to translational potential, focusing on epigenetic biomarkers and disease-modifying techniques designed to restore lysosomal function, rectify dopamine processing, and strategically exploit hormone pathways.