Intra-axonal protein synthesis in neurological disorders.

Functions of axonally translated proteins that are regulated by locally processed sncRNAs:

The long-term goal of this future research program is to identify and characterize molecular alterations underlying persistent state of spinal cord injury (SCI)-related pain conditions and ultimately to improve the management of spontaneous pain, hyperalgesia, and allodynia in patients with SCI. Chronic alterations in pain pathways after SCI were originally thought to be a direct consequence of damage to neurons in the spinal cord. However, more recently it has been shown that SCI can trigger persistent increases in neuronal excitability and spontaneous activity in primary afferent nociceptors that can lead to chronic pain in patients with SCI. Notably, rats with cervical hemicontusive SCI exhibit bilateral pain-related hypersensitivity to noxious stimuli, and primary afferent nociceptors in the lumbar region that are not directly injured from the SCI show persistent hyperexcitability and increased spontaneous activity. This suggests that the primary afferent nociceptors are central effectors of neuropathic pain after SCI. However, little is yet known about the molecular alterations underlying SCI-induced hyperexcitability and spontaneous activity in nociceptors. When the sciatic nerve is directly injured, levels of Nav1.8 protein and mRNA, a nociceptor-specific voltage-gated Na+ channel, do not change in the cell body but are elevated in axons of nociceptive neurons. This raises the possibility that post-transcriptional regulation of gene expression (e.g. axonal transport of mRNA or axonal translation) can result in increased pain. I speculate that selective knockdown of Nav1.8 suppresses spontaneous activity and reduces hypersensitivity and pain in experimental SCI. Our recent preliminary data indicate that a reduced level in axonal miRNA-455-3p could cause selective upregulation of Nav1.8 channel expression in the regenerating sciatic nerve (Fig 6). Therefore, I hypothesize that spinal cord injury leads to a persistent decrease in miRNA-455-3p in sensory neurons that are not directly affected by the SCI, thereby increasing expression of the Nav1.8 channel. This will lead to hyperexcitability and hyperalgesia in the sensory neurons and result in SCI-induced neuropathic pain.

Regulation of Nav1.8 mRNA by miRNA-455-3p. Left panel. Luciferase activity of vectors containing Nav1.8 mRNA’s 3’UTR, showing a significant reduction by miRNA-455-3p mimic. Right panel. Relative Nav1.8 mRNA level (Mean ± SD, n=3) to GAPDH mRNA in the DRGs transfected with miRNA-455-3p mimic.