Dysfunction of two lysosome degradation pathways of α-synuclein in Parkinson’s disease: potential therapeutic targets?

Parkinson’s disease (PD) is pathologically characterized by the presence of α-synuclein (α-syn)-positive intracytoplasmic inclusions named Lewy bodies in the dopaminergic neurons of the substantia nigra. A series of morbid consequences are caused by pathologically high amounts or mutant forms of α-syn, such as defects of membrane trafficking and lipid metabolism. In this review, we consider evidence that both point mutation and overexpression of α-syn result in aberrant degradation in neurons and microglia, and this is associated with the autophagy-lysosome pathway and endosome-lysosome system, leading directly to pathological intracellular aggregation, abnormal externalization and re-internalization cycling (and, in turn, internalization and re-externalization), and exocytosis. Based on these pathological changes, an increasing number of researchers have focused on these new therapeutic targets, aiming at alleviating the pathological accumulation of α-syn and re-establishing normal degradation.