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HSP27 Modulates Neuropathic Pain by Inhibiting P2X3 Degradation

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Abstract

The role of heat shock protein 27 (HSP27), a chaperone, in neuropathic pain after nerve injury has not been systematically surveyed despite its neuroprotective and regeneration-promoting effects. In this study, we found that HSP27 expression in sensory neurons of the dorsal root ganglia (DRG) mediated nerve injury–induced neuropathic pain. Neuropathic pain behaviors were alleviated by silencing HSP27 in the DRG of a rat spinal nerve ligation (SNL) model. Local injection of an HSP27-overexpression construct into the DRG of naïve rats elicited neuropathic pain behaviors. HSP27 interacted with a purinergic receptor, P2X3, and their expression patterns corroborated the induction and reversal of neuropathic pain according to two lines of evidence: colocalization immunohistochemically and immunoprecipitation biochemically. In a cell model cotransfected with HSP27 and P2X3, the degradation rate of P2X3 was reduced in the presence of HSP27. Such an alteration was mediated by reducing P2X3 ubiquitination in SNL rats and was reversed after silencing HSP27 in the DRGs of SNL rats. In summary, the interaction of HSP27 with P2X3 provides a new mechanism of injury-induced neuropathic pain that could serve as an alternative therapeutic target.

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Data Availability

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by grants from Ministry of Science and Technology (MOST 107–2320-B-002–043-MY3, MOST 107–3017-F-002–002), Ministry of Education (107L9014–2), National Health Research Institutes (NHRI-112BCCO-EB-232332), and National Taiwan University Hospital (UN112-UN0019).

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  1. Ti-Yen Yeh and Ming-Fong Chang contributed equally to this article.

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan

    Ti-Yen Yeh, Ming-Fong Chang & Sung-Tsang Hsieh

  2. School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan

    Yu-Yu Kan

  3. Akouos, Inc., Boston, MA, 02210, USA

    Hao Chiang

  4. Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan

    Sung-Tsang Hsieh

  5. Center of Precision Medicine, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan

    Sung-Tsang Hsieh

  6. Department of Neurology, National Taiwan University Hospital, Taipei, 10002, Taiwan

    Sung-Tsang Hsieh

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Contributions

Conceptualization: S.-T.H. Performed the experiments and conducted the analysis: T.-Y.Y., M.-F.C., H.-W.K., and H.C. Writing and editing: T.-Y.Y. and M.-F.G. Prepared figures: T.-Y.Y. and M.-F.G. Supervision: S.-T.H. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Sung-Tsang Hsieh.

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Yeh, TY., Chang, MF., Kan, YY. et al. HSP27 Modulates Neuropathic Pain by Inhibiting P2X3 Degradation. Mol Neurobiol 61, 707–724 (2024). https://doi.org/10.1007/s12035-023-03582-7

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