Dopamine-modified α-synuclein blocks chaperone-mediated autophagy

Marta Martinez-Vicente, Zsolt Talloczy, Susmita Kaushik, Ashish C. Massey, Joseph Mazzulli, Eugene V. Mosharov, Roberto Hodara, Ross Fredenburg, Du Chu Wu, Antonia Follenzi, William Dauer, Serge Przedborski, Harry Ischiropoulos, Peter T. Lansbury, David Sulzer, Ana Maria Cuervo*

*Corresponding author for this work

Research output: Contribution to journalArticle

440 Scopus citations

Abstract

Altered degradation of α-synuclein (α-syn) has been implicated in the pathogenesis of Parkinson disease (PD). We have shown that α-syn can be degraded via chaperone-mediated autophagy (CMA), a selective lysosomal mechanism for degradation of cytosolic proteins. Pathogenic mutants of α-syn block lysosomal translocation, impairing their own degradation along with that of other CMA substrates. While pathogenic α-syn mutations are rare, α-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 α-syn impair degradation of this protein by CMA but do not affect degradation of other substrates. Dopamine-modified α-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.

Original languageEnglish (US)
Pages (from-to)777-778
Number of pages2
JournalJournal of Clinical Investigation
Volume118
Issue number2
DOIs
StatePublished - Feb 1 2008

ASJC Scopus subject areas

  • Medicine(all)

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    Martinez-Vicente, M., Talloczy, Z., Kaushik, S., Massey, A. C., Mazzulli, J., Mosharov, E. V., Hodara, R., Fredenburg, R., Wu, D. C., Follenzi, A., Dauer, W., Przedborski, S., Ischiropoulos, H., Lansbury, P. T., Sulzer, D., & Cuervo, A. M. (2008). Dopamine-modified α-synuclein blocks chaperone-mediated autophagy. Journal of Clinical Investigation, 118(2), 777-778. https://doi.org/10.1172/JCI32806