Endogenous dopamine (DA) renders dopaminergic cells vulnerable to challenge of proteasome inhibitor MG132

Abstract

This study demonstrated that dopaminergic MN9D and PC12 cells were more vulnerable than non-dopaminergic N2A cells to the challenge by proteasome inhibitor MG132, which could be alleviated by reductants and alpha-methyl tyrosine (alpha-MT), a specific tyrosine hydroxylase inhibitor. Furthermore, challenging non-dopaminergic N2A cells with exogenous DA could aggravate MG132-induced cell viability decrease, which could be abrogated by reductants but not by alpha-MT. It was observed that alpha-MT could decrease endogenous DA content in dopaminergic MN9D and PC12 cells while N2A cells could take in exogenous DA into cytosol. The endogenous DA in dopaminergic cells was demonstrated to inhibit proteasome activity in the cells and further sensitize the proteasome to MG132 inhibition. In addition, the endogenous DA was also implicated for the increased level of lipid peroxidation and ubiquitinated proteins as well as inclusion bodies formation when non-dopaminergic cells were challenged with exogenous DA. Taken together it is proposed that endogenous DA in dopaminergic neurons could promote selective dopaminergic neurodegeneration, especially under the conditions of exopathic or idiopathic defects of ubiquitin–proteasome system (UPS), which may be abolished by reductant remedy.