Parkinson's disease(PD)is the most common neurodegenerative movement disease.It is featured by abnormal alphα-synuclein(α-syn)aggregation in dopaminergic neurons in the substantia nigra.Macroautophagy(autophagy)...Parkinson's disease(PD)is the most common neurodegenerative movement disease.It is featured by abnormal alphα-synuclein(α-syn)aggregation in dopaminergic neurons in the substantia nigra.Macroautophagy(autophagy)is an evolutionarily conserved cellular process for degradation of cellular contents,including protein aggregates,to maintain cellular homeostasis.Corynoxine B(Cory B),a natural alkaloid isolated from Uncaria rhynchophylla(Miq.)Jacks.,has been reported to promote the clearance ofα-syn in cell models by inducing autophagy.However,the molecular mechanism by which Cory B induces autophagy is not known,and theα-syn-lowering activity of Cory B has not been verified in animal models.Here,we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2.Depletion of HMGB1/2 impaired Cory B-induced autophagy.We showed for the first time that,similar to HMGB1,HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinaseⅢactivity both under basal and stimulated conditions.By applying cellular thermal shift assay,surface plasmon resonance,and molecular docking,we confirmed that Cory B directly binds to HMGB1/2 near the C106 site.Furthermore,in vivo studies with a wild-typeα-syn transgenic drosophila model of PD and an A53Tα-syn transgenic mouse model of PD,Cory B enhanced autophagy,promotedα-syn clearance and improved behavioral abnormalities.Taken together,the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinaseⅢactivity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.展开更多
基金supported by the National Natural Science Foundation of China(No.82271455)the Guangdong Basic and Applied Basic Research Foundation(No.2022A1515012416,China)+5 种基金the Science and Technology Development Fund,Macao SAR(No.0128/2019/A3,China)the Shenzhen Fundamental Research Program(No.SGDX20210823103804030,China)the University of Macao grants(No.MYRG2022-00094-ICMS,China)awarded to Jia-hong Lupartly supported by Hong Kong Health and Medical Research Fund(HMRF/17182551,HMRF/09203776,China)the Hong Kong General Research Fund(HKBU 12100618,HKBU 12101022,China)from Hong Kong Governmentthe Research Fund from Hong Kong Baptist University(HKBU/RC-IRCs/17-18/03,IRCMS/19-20/H02,China)awarded to Min Li。
文摘Parkinson's disease(PD)is the most common neurodegenerative movement disease.It is featured by abnormal alphα-synuclein(α-syn)aggregation in dopaminergic neurons in the substantia nigra.Macroautophagy(autophagy)is an evolutionarily conserved cellular process for degradation of cellular contents,including protein aggregates,to maintain cellular homeostasis.Corynoxine B(Cory B),a natural alkaloid isolated from Uncaria rhynchophylla(Miq.)Jacks.,has been reported to promote the clearance ofα-syn in cell models by inducing autophagy.However,the molecular mechanism by which Cory B induces autophagy is not known,and theα-syn-lowering activity of Cory B has not been verified in animal models.Here,we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2.Depletion of HMGB1/2 impaired Cory B-induced autophagy.We showed for the first time that,similar to HMGB1,HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinaseⅢactivity both under basal and stimulated conditions.By applying cellular thermal shift assay,surface plasmon resonance,and molecular docking,we confirmed that Cory B directly binds to HMGB1/2 near the C106 site.Furthermore,in vivo studies with a wild-typeα-syn transgenic drosophila model of PD and an A53Tα-syn transgenic mouse model of PD,Cory B enhanced autophagy,promotedα-syn clearance and improved behavioral abnormalities.Taken together,the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinaseⅢactivity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.
