Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy.
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.
Martinez-Vicente
Marta
M
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Yeshiva University, New York, New York 10461, USA.
Talloczy
Zsolt
Z
Kaushik
Susmita
S
Massey
Ashish C
AC
Mazzulli
Joseph
J
Mosharov
Eugene V
EV
Hodara
Roberto
R
Fredenburg
Ross
R
Wu
Du-Chu
DC
Follenzi
Antonia
A
Dauer
William
W
Przedborski
Serge
S
Ischiropoulos
Harry
H
Lansbury
Peter T
PT
Sulzer
David
D
Cuervo
Ana Maria
AM
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*
D018832:Molecular Chaperones; D051844:alpha-Synuclein; D004298:Dopamine