Molecular Mechanisms of Autophagy-Lysosome Dysfunction in the Pathogenesis and Progression of Parkinson's Disease

Autophagy-lysosome dysfunction is a major molecular feature of Parkinson's disease because it connects impaired α-synuclein clearance, mitochondrial damage, lysosomal enzyme insufficiency, vesicular trafficking defects, and neuroinflammatory activation. Dopaminergic neurons are particularly dependent on effective autophagic flux and lysosomal degradation owing to their post-mitotic state, high metabolic load, extensive axonal architecture, and vulnerability to oxidative stress. Work from the last several years has refined the understanding of Parkinson's disease from a protein aggregation disorder into a network disease involving macroautophagy, chaperone-mediated autophagy, mitophagy, lysosomal acidification, hydrolase activity, lipid metabolism, and stress-responsive transcriptional control. Genetic and mechanistic evidence involving SNCA, GBA1, LRRK2, PINK1, PRKN, VPS35, LAMP2A, cathepsins, and TFEB further supports this integrated view. This review summarizes recent advances in the molecular basis of the autophagy-lysosome system, the mechanisms through which its dysfunction promotes α-synuclein pathology and neuronal injury, and the therapeutic strategies aimed at restoring degradative capacity in Parkinson's disease. Emphasis is placed on the GBA1/GCase axis, LRRK2-dependent lysosomal stress responses, PINK1/Parkin-mediated mitophagy, TFEB-regulated lysosomal biogenesis, and emerging aggregate-targeted clearance approaches.