In Japan, which is now an ultra-aged society, overcoming the challenges of treating peripheral neuropathy in the elderly is an urgent issue. We previously demonstrated that expression of the transcription factor REST (RE1-silencing transcription factor) increases with age in peripheral nerves, while expression of the axon regeneration marker GAP43 decreases. In this study, REST-overexpressing (REST-OE) cells were used to investigate the effect of REST on the GAP43 expression mechanism in vitro.

REST-OE cells were constructed using fibroblast cell lines and the expression of molecular of JAK1/STAT3 pathway involved in GAP43 expression. Furthermore, REST-OE cells were cultures with GP130 agonist and the expression of GAP43 was investigated.

GAP43 expression was significantly decreased in REST-OE cells compared to the control (P=0.016). In addition, expression of the JAK1/STAT3 pathway was significantly decreased in REST-OE cells compared to the control (GP130, JAK1, and phosphorylated STAT3). In other words, under the high REST expression, the decrease of GP130 expression, which is involved in GAP43 expression, led to decreased molecular expression of the JAK1/STAT3 pathway and decreased GAP43 expression. Furthermore, when REST-OE cells were cultured under administration of a GP130 agonist, GAP43 expression was significantly increased compared to the non-administration group (P=0.0018).

It has been reported that peripheral nerve axon regeneration is impaired in GP130 deficiency. The results of this study suggest that REST controls axon regeneration via the JAK1/STAT3 pathway mediated by GP130. In addition, administration of a GP130 agonist increased GAP43 expression, suggesting that GP130 may be a therapeutic target for age-related decrease in peripheral nerve axon regeneration.

The transcription factor REST may be involved the pathogenesis of age-related decrease in peripheral nerve axon regeneration.