Dopamine-modified α-synuclein blocks chaperone-mediated autophagy

TLDR

Altered degradation of α‑syn is implicated in Parkinson disease, and posttranslational modifications may underlie its accumulation in cytosolic aggregates in most forms of PD. The study proposes that dopamine‑induced inhibition of chaperone‑mediated autophagy may explain selective degeneration of Parkinson disease dopaminergic neurons. The authors used mouse ventral medial neuron cultures, SH‑5Y cells, and isolated mouse lysosomes to show that most posttranslational modifications of α‑syn impair its CMA degradation, while dopamine‑modified α‑syn is poorly degraded and blocks other CMA substrates. The study found that α‑syn is normally degraded by CMA, but pathogenic mutants and most posttranslational modifications impair its degradation, and dopamine‑modified α‑syn is poorly degraded and additionally blocks degradation of other CMA substrates.

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.