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

Acta Pharmacologica Sinica volume 44, pages 940–953 (2023)Cite this article

Abstract

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.

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Fig. 1: VHL knockdown prevents behavioral and pathological abnormalities in PD model mice.
Fig. 2: Genetic and pharmacological inhibition of VHL alleviates parkinsonian toxicant-induced neurodegeneration in cell and nematode models.
Fig. 3: Evidence for the role of DVL-2 in VHL inactivation conferring protection against PD.
Fig. 4: DVL-2 overexpression mimics VHL inactivation followed by β-catenin axis enhancement and confers protection against PD.
Fig. 5: β-catenin plays a key role in mediating the alleviation effects of VHL inhibition on the degeneration of dopaminergic neurons caused by mitochondrial dysfunction.
Fig. 6: Design and screening of the competing peptide targeting VHL/DVL-2 and evaluation of its protection against PD.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Nos. 82173728, 81872850, 82073755 and 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).

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Author notes

  1. These authors contributed equally: Jie Shen, Qian Zha, Qian-hua Yang

Authors and Affiliations

  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

    Jie Shen, Qian Zha, Qian-hua Yang, Yue-qian Zhou, Xiao Liang, Ying-jie Chen, Gui-xia Qi, Wen-bing Yao, Xiang-dong Gao & Song Chen

  2. Department of Chemistry, China Pharmaceutical University, Nanjing, 211198, China

    Xiao-jin Zhang

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Contributions

JS: Conceptualization, Methodology, Investigation, Writing-Original Draft, Writing-Review and Editing. QZ: Conceptualization, Methodology, Investigation, Writing-Original Draft, Writing-Review and Editing. QHY: Conceptualization, Methodology, Investigation, Writing-Original Draft, Writing-Review and Editing. YQZ: Investigation. XL: Investigation. YJC: Investigation. GXQ: Investigation. XJZ: Investigation. WBY: Conceptualization, Writing-Review and Editing, Funding acquisition, Supervision. XDG: Conceptualization, Writing-Review and Editing, Funding acquisition, Supervision. SC: Conceptualization, Writing-Review and Editing, Funding acquisition, Supervision.

Corresponding authors

Correspondence to Wen-bing Yao, Xiang-dong Gao or Song Chen.

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The authors declare no competing interests. XDG, SC, QHY, YQZ and WBY have applied for patent related to this study.

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Shen, J., Zha, Q., Yang, Qh. et al. Inhibiting von Hippel‒Lindau protein-mediated Dishevelled ubiquitination protects against experimental parkinsonism. Acta Pharmacol Sin 44, 940–953 (2023). https://doi.org/10.1038/s41401-022-01014-1

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