2,5-Hexanedione induces dopaminergic neurodegeneration through integrin α(M)β2/NADPH oxidase axis-mediated microglial activation

Recent study demonstrated that chronic exposure to solvents increases the risk of Parkinson’s disease (PD), the second most common neurodegenerative disorder characterized by progressive dopaminergic neurodegeneration in the substantia nigra (SN). n-Hexane, a widely used organic solvent, displays central-peripheral neurotoxicity, which is mainly mediated by its active metabolite, 2,5-hexanedione (HD). However, whether HD exposure contributes to PD remains unclear. In this study, we found that rats exposed to HD displayed progressive dopaminergic neurodegeneration in the nigrostriatal system. Microglial activation was also detected in HD-treated rats, which occurred prior to degeneration of dopaminergic neurons. Moreover, depletion of microglia markedly reduced HD-induced dopaminergic neurotoxicity. Mechanistic study revealed an essential role of microglial integrin α(M)β(2)-NADPH oxidase (NOX2) axis in HD-elicited neurotoxicity. HD activated NOX2 by inducing membrane translocation of NOX2 cytosolic subunit, p47(phox). Integrin α(M)β(2) was critical for HD-induced NOX2 activation since inhibition or genetic deletion of α(M)β(2) attenuated NOX2-generated superoxide and p47(phox) membrane translocation in response to HD. Src and Erk, two downstream signals of α(M)β(2), were recognized to bridge HD/α(M)β(2)-mediated NOX2 activation. Finally, pharmacological inhibition of α(M)β(2)-NOX2 axis attenuated HD-induced microglial activation and dopaminergic neurodegeneration. Our findings revealed that HD exposure damaged nigrostriatal dopaminergic system through α(M)β(2)-NOX2 axis-mediated microglial activation, providing, for the first time, experimental evidence for n-hexane exposure contributing to the etiology of PD.