The Overcrowded Crossroads: Mitochondria, Alpha-Synuclein, and the Endo-Lysosomal System Interaction in Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide, mainly affecting the elderly. The disease progresses gradually, with core motor presentations and a multitude of non-motor manifestations. There are two neuropathological hallmarks of PD, the dopaminergic neuronal loss and the alpha-synuclein-containing Lewy body inclusions in the substantia nigra. While the exact pathomechanisms of PD remain unclear, genetic investigations have revealed evidence of the involvement of mitochondrial function, alpha-synuclein (alpha -syn) aggregation, and the endo-lysosomal system, in disease pathogenesis. Due to the high energy demand of dopaminergic neurons, mitochondria are of special importance acting as the cellular powerhouse. Mitochondrial dynamic fusion and fission, and autophagy quality control keep the mitochondrial network in a healthy state. Should defects of the organelle occur, a variety of reactions would ensue at the cellular level, including disrupted mitochondrial respiratory network and perturbed calcium homeostasis, possibly resulting in cellular death. Meanwhile, alpha -syn is a presynaptic protein that helps regulate synaptic vesicle transportation and endocytosis. Its misfolding into oligomeric sheets and fibrillation is toxic to the mitochondria and neurons. Increased cellular oxidative stress leads to alpha -syn accumulation, causing mitochondrial dysfunction. The proteasome and endo-lysosomal systems function to regulate damage and unwanted waste management within the cell while facilitating the quality control of mitochondria and alpha -syn. This review will analyze the biological functions and interactions between mitochondria, alpha -syn, and the endo-lysosomal system in the pathogenesis of PD.