Genetic architecture and molecular pathogenesis of Parkinson's disease: emerging mechanisms and therapeutic targets

According to the Global Burden of Disease Study 2023, Parkinson's disease (PD) affects an estimated 11.67 million people worldwide, a progressive neurodegenerative condition marked by the accumulation of Lewy bodies containing α-synuclein and the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Over the past ten years, advances in genetic and molecular research have shown that PD pathogenesis involves interrelated mechanisms such as impaired protein homeostasis, mitochondrial dysfunction, oxidative stress, defects in lysosomal-autophagic pathways, and chronic neuroinflammation, which go beyond dopaminergic neuronal loss. This review summarizes new data about major genes associated with monogenic and polygenic forms of PD, including SNCA, LRRK2, PRKN, PINK1, DJ-1 (PARK7), GBA1, VPS35, ATP13A2, FBXO7, and the GWAS-prioritized risk genes TMEM175, SCARB2, CTSB, RIT2, DYRK1A, and BAG3, together with the molecular pathways disrupted by these genetic alterations in light of current evidence. The polygenic architecture of PD and ancestry-related variation in genetic risk are also discussed. α-synuclein aggregation and proteostasis networks, oxidative stress, autophagy and mitophagy failure, neuroinflammation, mitochondrial quality control, and epigenetic regulation are all given special attention. Apart from traditional dopaminergic treatments, new therapeutic approaches such as immunotherapies targeting α-synuclein, gene therapies mediated by adeno-associated virus (AAV), induced pluripotent stem cell (iPSC)-based methods, and genotype-guided precision medicine are critically examined. A more comprehensive understanding of the molecular mechanisms underlying PD is expected to facilitate the development of reliable biomarkers and accelerate the clinical translation of disease-modifying therapies.