title: Dysfunction of two lysosome degradation pathways of α-synuclein in Parkinson's disease: potential therapeutic targets?
abstract: 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.
authors.affiliation: Department of Neurology & Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Tian-Fang
authors.initials: TF
authors.lastname: Jiang
authors.forename: Sheng-Di
authors.initials: SD
authors.lastname: Chen
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D016503:Drug Delivery Systems / Q000379:methods*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000235:genetics* / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; D051844:alpha-Synuclein