Details

Autor(en) / Beteiligte

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

Titel

Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy

Ist Teil von

• The Journal of clinical investigation, 2008-02, Vol.118 (2), p.777-788

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2008

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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.