Local proteins associated with methamphetamine-induced nigrostriatal dopaminergic neurotoxicity

Abstract The present study aimed to examine the proteins involved in the methamphetamine (MA)‐induced nigrostriatal dopaminergic toxicity. Infusion of anisomycin into striatum and substantia nigra both abolished the MA‐induced striatal dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) depletions, indicating a critical role of local protein synthesis in determining such dopaminergic toxicity. Moreover, local protein synthesis blockade reversed this neurotoxicity via a temperature‐independent mechanism. We then employed a proteomic approach, two‐dimensional gel electrophoresis (2‐DE) in conjunction with mass spectrometry analysis, to identify the protein candidates associated with the MA‐induced neurotoxicity. In striatal samples, 2‐DE analysis revealed that the intensities of nine protein spots were altered by MA treatment. Mass spectrometry analysis allowed us to identify five proteins, including an up‐regulated protein, α‐synuclein, and four down‐regulated proteins, ATPase, F‐actin capping protein β subunit, ubiquitin carboxy‐terminal hydrolase/PGP 9.5, and peroxidase. MA‐altered expression levels of α‐synuclein and ubiquitin carboxy‐terminal hydrolase/PGP 9.5 in striata were confirmed by western blotting analysis. Taken together, these results suggest that local up‐regulation of α‐synuclein and down‐regulation of ubiquitin carboxy‐terminal hydrolase/PGP 9.5 could be linked to the MA‐induced dopaminergic terminal toxicity.