FUS Contributes to Nerve Injury-Induced Nociceptive Hypersensitivity by Activating NF-KB Pathway in Primary Sensory Neurons

Dysregulation of pain-associated genes in the dorsal root ganglion (DRG) is considered to be a molecular basis of neuropathic pain genesis. Fused in sarcoma (FUS), a DNA/RNA-binding protein, is a critical regulator of gene expression. However, whether it contributes to neuropathic pain is unknown. This study showed that peripheral nerve injury caused by the fourth lumbar (L4) spinal nerve ligation (SNL) or chronic constriction injury (CCI) of the sciatic nerve produced a marked increase in the expression of FUS protein in injured DRG neurons. Blocking this increase through microinjection of the adeno-associ-ated virus (AAV) 5-expressing Fus shRNA into the ipsilateral L4 DRG mitigated the SNL-induced nociceptive hypersensitiv-ities in both male and female mice. This microinjection also alleviated the SNL-induced increases in the levels of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) and glial fibrillary acidic protein (GFAP) in the ipsilateral L4 dorsal horn. Furthermore, mimicking this increase through microinjection of AAV5 expressing full-length Fus mRNA into unilateral L3/4 DRGs produced the elevations in the levels of p-ERK1/2 and GFAP in the dorsal horn, enhanced responses to mechanical, heat and cold stimuli, and induced the spontaneous pain on the ipsilateral side of both male and female mice in the absence of SNL. Mechanistically, the increased FUS activated the NF-KB signaling pathway by promoting the translocation of p65 into the nucleus and phosphorylation of p65 in the nucleus from injured DRG neurons. Our results indicate that DRG FUS contributes to neuropathic pain likely through the activation of NF-KB in primary sensory neurons.

Automated summary

This study investigates the role of Fused in sarcoma (FUS) protein in neuropathic pain. The researchers found that peripheral nerve injury increased the expression of FUS protein in injured dorsal root ganglion (DRG) neurons. Blocking this increase reduced nociceptive hypersensitivities and the levels of certain proteins involved in pain processing. On the other hand, mimicking this increase induced pain-like behaviors and increased pain-related protein levels. Mechanistically, the increased FUS activated the NF-KB signaling pathway. Overall, these findings suggest that DRG FUS contributes to neuropathic pain through the activation of NF-KB in primary sensory neurons.