Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal funct...Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.展开更多
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...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.展开更多
基金supported by the National Natural Science Foundation of China,No.82201582(to QT)Scientific and Technological Research Program of Chongqing Municipal Education Commission,No.KJQN202200457(to QT)+3 种基金General Project of Changqing Natural Science Foundation,No.cstc2021jcyjmsxmX0442(to ZL)CQMU Program for Youth Innovation in Future Medicine,No.W0044(to ZD and GH)Direct Research Project for PhD of Chongqing,No.CSTB2022BSXM-JCX0051(to ZL)the Project of the Top-Notch Talent Cultivation Program For the Graduate Students of Chongqing Medical University,No.BJRC202310(to CG)。
文摘Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.
基金Key Technologies Research and Development Program of Shandong Province (2017GSF18171,2018GSF118139).
文摘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.
