title: α-Synuclein interferes with the ESCRT-III complex contributing to the pathogenesis of Lewy body disease.
abstract: α-Synuclein (α-syn) has been implicated in neurological disorders with parkinsonism, including Parkinson's disease and Dementia with Lewy body. Recent studies have shown α-syn oligomers released from neurons can propagate from cell-to-cell in a prion-like fashion exacerbating neurodegeneration. In this study, we examined the role of the endosomal sorting complex required for transport (ESCRT) pathway on the propagation of α-syn. α-syn, which is transported via the ESCRT pathway through multivesicular bodies for degradation, can also target the degradation of the ESCRT protein-charged multivesicular body protein (CHMP2B), thus generating a roadblock of endocytosed α-syn. Disruption of the ESCRT transport system also resulted in increased exocytosis of α-syn thus potentially increasing cell-to-cell propagation of synuclein. Conversely, delivery of a lentiviral vector overexpressing CHMP2B rescued the neurodegeneration in α-syn transgenic mice. Better understanding of the mechanisms of intracellular trafficking of α-syn might be important for understanding the pathogenesis and developing new treatments for synucleinopathies.
authors.affiliation: Department of Neuroscience and.
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.affiliation: Department of Neuroscience and Department of Medicine, College of Medicine, Seoul National University, Seoul 110-799, Korea.
authors.forename: Changyoun
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Neuroscience and.
authors.forename: Tania
authors.initials: T
authors.lastname: Gonzalez
authors.affiliation: Department of Neuroscience and.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Bisquertt
authors.affiliation: Department of Neuroscience and.
authors.forename: Christina
authors.initials: C
authors.lastname: Patrick
authors.affiliation: Department of Neuroscience and.
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.affiliation: Department of Neuroscience and.
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.affiliation: Department of Medicine, College of Medicine, Seoul National University, Seoul 110-799, Korea.
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Neuroscience and.
authors.forename: Paula
authors.initials: P
authors.lastname: Desplats
authors.affiliation: Department of Neuroscience and Department of Pathology, University of California, San Diego, San Diego, CA 92103, USA and emasliah@ucsd.edu.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002460:Cell Line; D004195:Disease Models, Animal; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology; D020961:Lewy Body Disease / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D051844:alpha-Synuclein