2,5-Hexanedione induces dopaminergic neurodegeneration through integrin αMβ2/NADPH oxidase axis-mediated microglial activation

作者：Zhang, Cong; Hou, Liyan; Yang, Jie; Che, Yuning; Sun, Fuqiang; Li, Huihua; Wang, Qingshan^*

来源：Cell Death & Disease, 2018, 9(2): 60.

DOI：10.1038/s41419-017-0091-7

• NADPH OXIDASE
• PARKINSONS-DISEASE
• N-HEXANE
• OCCUPATIONAL EXPOSURE
• SUBSTANTIA-NIGRA
• OXIDATIVE STRESS
• RECEPTOR
• PHOSPHORYLATION
• SRC
• ALPHA

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 alpha(M)beta(2)-NADPH oxidase (NOX2) axis in HD-elicited neurotoxicity. HD activated NOX2 by inducing membrane translocation of NOX2 cytosolic subunit, p47(phox). Integrin alpha(M)beta(2) was critical for HD-induced NOX2 activation since inhibition or genetic deletion of alpha(M)beta 2 attenuated NOX2-generated superoxide and p47(phox) membrane translocation in response to HD. Src and Erk, two downstream signals of alpha(M)beta(2), were recognized to bridge HD/alpha(M)beta(2)-mediated NOX2 activation. Finally, pharmacological inhibition of alpha(M)beta(2)-NOX2 axis attenuated HD-induced microglial activation and dopaminergic neurodegeneration. Our findings revealed that HD exposure damaged nigrostriatal dopaminergic system through alpha(M)beta(2)-NOX2 axis-mediated microglial activation, providing, for the first time, experimental evidence for n-hexane exposure contributing to the etiology of PD.

• 出版日期2018-1-19
• 单位大连医科大学