Dopamine induces proteasome inhibition in neural PC12 cell line

The autoxidation and enzymatic catabolism of dopamine results in the genera tion of reactive oxygen species (ROS), which may possibly contribute to oxi dative stress in multiple neurodegenerative disorders. Recent studies indic ate that proteasome inhibition occurs in numerous neurodegenerative conditi ons, possibly as the result of oxidative stress, although the effects of do pamine on proteasome activity have not been determined. In the present stud y we examined the effects of dopamine on proteasome activity in the neural PC12 cell line. Application of dopamine induced a dose- and time-dependent decrease in proteasome activity, which occurred prior to cell death. Applic ation of an antioxidant (gluthathione monoethyl ester), monoamine oxidase i nhibitors (deprenyl, clogyline, paragyline), or an inhibitor of dopamine up take (nomifensine) attenuated dopamine toxicity and dopamine-induced protea some impairment. Application of the proteasome inhibitor lactacystin increa sed the toxicity of dopamine and the levels of protein oxidation following administration of dopamine. Together, these data indicate that dopamine ind uces proteasome inhibition that is dependent, in part, on ROS and dopamine uptake, and suggest a possible role for proteasome inhibition in dopamine t oxicity. (C) 2000 Elsevier Science Inc.