TY - JOUR AU - Shen Jie AU - Zha Qian AU - Yang Qian-hua AU - Zhou Yue-qian AU - Liang Xiao AU - Chen Ying-jie AU - Qi Gui-xia AU - Zhang Xiao-jin AU - Yao Wen-bing AU - Gao Xiang-dong AU - Chen Song PY - 2023 TI - Inhibiting von Hippel‒Lindau protein-mediated Dishevelled ubiquitination protects against experimental parkinsonism JF - Acta Pharmacologica Sinica; Vol 44, No 5 (May 2023): Acta Pharmacologica Sinica Y2 - 2023 KW - N2 - 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 of β-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. UR - http://www.chinaphar.com/article/view/10817