Integrated Mechanisms Driving Parkinson's Disease Pathogenesis

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of aggregated α-synuclein within Lewy bodies and Lewy neurites.Although traditionally defined by its motor manifestations, PD is now recognised as a multisystem disorder involving disruptions in neuronal homeostasis, including mitochondrial quality control, lysosomal degradation, synaptic vesicle trafficking, autophagy, redox balance, and neuroimmune signalling.Genetic studies have identified mutations in SNCA, LRRK2, GBA1, PINK1, PRKN, DJ-1, VPS35, and ATP13A2 that converge on intracellular pathways essential for neuronal integrity.Accumulating evidence indicates that α-synuclein aggregation, defective mitophagy, lysosomal dysfunction, oxidative stress, and chronic neuroinflammation are interconnected through self-amplifying pathogenic networks that progressively impair neuronal function and survival.This review synthesises current genetic and mechanistic insights into how disease-associated mutations and dysregulated cellular pathways contribute to PD pathogenesis.A comprehensive understanding of these interconnected mechanisms may facilitate the development of disease-modifying therapies targeting common pathogenic processes across mitochondrial, lysosomal, synaptic, and inflammatory pathways.Furthermore, emerging biomarker research may improve early diagnosis, patient stratification, therapeutic monitoring, and personalised intervention strategies for PD in the future.