Inhibiting von Hippel‒Lindau protein-mediated Dishevelled ubiquitination protects against experimental parkinsonism  

作　　者：Jie Shen Qian Zha Qian-hua Yang Yue-qian Zhou Xiao Liang Ying-jie Chen Gui-xia Qi Xiao-jin Zhang Wen-bing Yao Xiang-dong Gao Song Chen 

机构地区：[1]Jiangsu Key Laboratory of Druggability of Biopharmaceuticals,State Key Laboratory of Natural Medicines,School of Life Science and Technology,China Pharmaceutical University,Nanjing 211198,China [2]Department of Chemistry,China Pharmaceutical University,Nanjing 211198,China

出　　处：《Acta Pharmacologica Sinica》2023年第5期940-953,共14页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.82173728,81872850,82073755,81673435);the"Double First-Class"University Project(No.CPU2018GF08);Qing Lan Project of Jiangsu Province and PAPD(A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions).

摘　　要：Dopaminergic neuron degeneration is a hallmark of Parkinson’s disease(PD).We previously reported that the inactivation of von Hippel‒Lindau(VHL)alleviated dopaminergic neuron degeneration in a C.elegans model.In this study,we investigated the specific effects of VHL loss and the underlying mechanisms in mammalian PD models.For in vivo genetic inhibition of VHL,AAV-Vhl-shRNA was injected into mouse lateral ventricles.Thirty days later,the mice received MPTP for 5 days to induce PD.Behavioral experiments were conducted on D1,D3,D7,D14 and D21 after the last injection,and the mice were sacrificed on D22.We showed that knockdown of VHL in mice significantly alleviated PD-like syndromes detected in behavioral and biochemical assays.Inhibiting VHL exerted similar protective effects in MPP^(+)-treated differentiated SH-SY5Y cells and the MPP^(+)-induced C.elegans PD model.We further demonstrated that VHL loss-induced protection against experimental parkinsonism was independent of hypoxia-inducible factor and identified the Dishevelled-2(DVL-2)/β-catenin axis as the target of VHL,which was evolutionarily conserved in both C.elegans and mammals.Inhibiting the function of VHL promoted the stability ofβ-catenin by reducing the ubiquitination and degradation of DVL-2.Thus,in vivo overexpression of DVL-2,mimicking VHL inactivation,protected against PD.We designed a competing peptide,Tat-DDF-2,to inhibit the interaction between VHL and DVL-2,which exhibited pharmacological potential for protection against PD in vitro and in vivo.We propose the therapeutic potential of targeting the interaction between VHL and DVL-2,which may represent a strategy to alleviate neurodegeneration associated with PD.

关 键 词：Parkinson’s disease von Hippel‒Lindau Dishevelled-2 peptide MPTP MPP^(+) 

分 类 号：R965[医药卫生—药理学]