Histone deacetylase 6 mediated NALP3 inflammasome activation contributes to dopaminergic injury in experimental models of Parkinson disease

摘要

OBJECTIVE To investigate the mechanisms of histone deacetylase 6(HDAC6)deacetylation activity on NALP3 inflammasome activation and explore the protective effect s of pharmacological inhibition of HDAC6 on dopaminergic injury.METHODS In vitro and in vivo6-OHDA induced Parkinson disease(PD) model was used.To distinguish the effect of deacetylase catalytic domains of HDAC6,we used a specific HDAC6 inhibitor tubastatin A(TBA),siRNAHDAC6,and pcDNA-HDAC6-FLAG plasmid.First,the role of pharmacological inhibition or siRNA or overexpression of HDAC6 on NALP3 inflammasome and cell death was explored by using Western blotting,TUNEL,and flow cytometric analysis.Then,the acetylation level of peroxiredoxin 2(Prx2) and the production of reactive oxygen species(ROS) in cells under different treatments was examined by using immunoprecipitation and DCFH-DA fluorescence assay.The effects of TBA on neuroinflammation and nigrostriatal dopaminergic system in vivo was further investigated by using Western blotting,immunohistochemistry and HPLC analysis.RESULTS TBA remarkably inhibited 6-OHDA induced NALP3 inflammasome activation,reduced dopaminergic neurodegeneration and neuroinflammation as demonstrated by increased TH-positive neurons,striatal levels of DA and its metabolites,and decreased gliocyte proliferation.TBA recovered acetylation of Prx2,and reduced ROS production,which was associated with decreased NALP3 inflammasome activation.CONCLUSION HDAC6 may medicate deacetylation of Prx2 contributes to NALP3 inflammasome activation in PD pathology,suggesting that the development of specific pharmacological inhibitors of HDAC6 be required for this kind of disease.