title: Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy.
abstract: Altered degradation of alpha-synuclein (alpha-syn) has been implicated in the pathogenesis of Parkinson disease (PD). We have shown that alpha-syn can be degraded via chaperone-mediated autophagy (CMA), a selective lysosomal mechanism for degradation of cytosolic proteins. Pathogenic mutants of alpha-syn block lysosomal translocation, impairing their own degradation along with that of other CMA substrates. While pathogenic alpha-syn mutations are rare, alpha-syn undergoes posttranslational modifications, which may underlie its accumulation in cytosolic aggregates in most forms of PD. Using mouse ventral medial neuron cultures, SH-SY5Y cells in culture, and isolated mouse lysosomes, we have found that most of these posttranslational modifications of alpha-syn impair degradation of this protein by CMA but do not affect degradation of other substrates. Dopamine-modified alpha-syn, however, is not only poorly degraded by CMA but also blocks degradation of other substrates by this pathway. As blockage of CMA increases cellular vulnerability to stressors, we propose that dopamine-induced autophagic inhibition could explain the selective degeneration of PD dopaminergic neurons.
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Yeshiva University, New York, New York 10461, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Martinez-Vicente
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Talloczy
authors.forename: Susmita
authors.initials: S
authors.lastname: Kaushik
authors.forename: Ashish C
authors.initials: AC
authors.lastname: Massey
authors.forename: Joseph
authors.initials: J
authors.lastname: Mazzulli
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Mosharov
authors.forename: Roberto
authors.initials: R
authors.lastname: Hodara
authors.forename: Ross
authors.initials: R
authors.lastname: Fredenburg
authors.forename: Du-Chu
authors.initials: DC
authors.lastname: Wu
authors.forename: Antonia
authors.initials: A
authors.lastname: Follenzi
authors.forename: William
authors.initials: W
authors.lastname: Dauer
authors.forename: Serge
authors.initials: S
authors.lastname: Przedborski
authors.forename: Harry
authors.initials: H
authors.lastname: Ischiropoulos
authors.forename: Peter T
authors.initials: PT
authors.lastname: Lansbury
authors.forename: David
authors.initials: D
authors.lastname: Sulzer
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Cuervo
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D004298:Dopamine / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018832:Molecular Chaperones / Q000378:metabolism*; D010300:Parkinson Disease / Q000209:etiology* / Q000473:pathology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051381:Rats; D017208:Rats, Wistar; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; D051844:alpha-Synuclein; D004298:Dopamine