Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (9): 2682-2696.doi: 10.4103/NRR.NRR-D-23-01539

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Protein arginine methyltransferase-6 regulates heterogeneous nuclear ribonucleoprotein-F expression and is a potential target for the treatment of neuropathic pain

Xiaoyu Zhang1, 2, 3, #, Yuqi Liu2, #, Fangxia Xu2, #, Chengcheng Zhou2 , Kaimei Lu2 , Bin Fang2 , Lijuan Wang2, *, Lina Huang2, *, Zifeng Xu1, 3, *   

  1. 1 Department of Anesthesiology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;  2 Department of Anesthesiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;  3 Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
  • Online:2025-09-15 Published:2024-12-30
  • Contact: Zifeng Xu, MD, PhD, xuzf@shsmu.edu.cn; Lina Huang, MD, PhD, lina.huang@shgh.cn; Lijuan Wang, MD, PhD, novjul0815@163.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 82001178 (to LW), 81901129 (to LH), 82001175 (to FX); Shanghai Sailing Program, No. 20YF1439200 (to LW); the Natural Science Foundation of Shanghai, China, No. 23ZR1450800 (to LH); and the Fundamental Research Funds for the Central Universities, No. YG2023LC15 (to ZX).

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Abstract: Protein arginine methyltransferase-6 participates in a range of biological functions, particularly RNA processing, transcription, chromatin remodeling, and endosomal trafficking. However, it remains unclear whether protein arginine methyltransferase-6 modifies neuropathic pain and, if so, what the mechanisms of this effect. In this study, protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model, chronic constriction injury model and bone cancer pain model, using immunohistochemistry, western blotting, immunoprecipitation, and label-free proteomic analysis. The results showed that protein arginine methyltransferase-6 mostly co-localized with β-tubulin III in the dorsal root ganglion, and that its expression decreased following spared nerve injury, chronic constriction injury and bone cancer pain. In addition, PRMT6 knockout (Prmt6–/–) mice exhibited pain hypersensitivity. Furthermore, the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression. Moreover, when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury, increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn, and the response to mechanical stimuli was enhanced. Mechanistically, protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F. Additionally, protein arginine methyltransferase-6-mediated modulation of heterogeneous nuclear ribonucleoprotein-F expression required amino acids 319 to 388, but not classical H3R2 methylation. These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target for the treatment of peripheral neuropathic pain.

Key words: dorsal root ganglion,  heterogeneous nuclear ribonucleoprotein F,  neuropathic pain,  protein arginine methyltransferase-6,  sensory neurons