Dopamine (DA) induced irreversible proteasome inhibition via DA derived quinones

Abstract

This study demonstrated that DA and its oxidative metabolites: H₂O₂ and aminochrome (AM), cyclized DA quinones, could all directly inhibit proteasome activity. DA and AM, especially AM, could induce intensive and irreversible proteasome inhibition, whereas proteasome inhibition induced by H₂O₂ was weaker and GSH reversible. It was concluded that DA induced irreversible proteasome inhibition via DA-derived quinones, rather than through small molecular weight ROS. The AM was also more toxic than H₂O₂ to dopaminergic MN9D cells. Furthermore the cytotoxicity and proteasome inhibition induced by DA, AM and H₂O₂ could be abrogated by GSH, ascorbic acid (AA), Vitamin E, SOD (superoxidase dismutase) or CAT (catalase) with different profiles. Only GSH was potent to abrogate DA, AM or H₂O₂-induced cell toxicity and proteasome inhibition, as well as to reverse H₂O₂-induced proteosome inhibition. Therefore, therapeutic strategies to increase GSH level or to use GSH substitutes should function to control PD onset and development.

• Aminochrome
• dopamine
• GSH
• H₂O₂
• Parkinson's disease
• proteasome inhibition