Age‑related changes in endoplasmic reticulum stress response‑associated protein expression in rat tibial nerves.

In age-related peripheral neurodegeneration, changes in the promotion or inhibition of endoplasmic reticulum (ER) stress response related to the ubiquitin-proteasome degradation system (UPS), autophagy and apoptosis signaling factors during aging remain unclear. In the present study, the expression of ER stress response signaling-related protein factors was examined in tibial nerves during aging in rats. Tibial nerves were extracted from continuously housed rats at 20, 50, 70, 90 and 105 weeks of age. Expression of factors associated with ER stress-related degradation, including X-box binding protein 1 (XBP1s), eukaryotic translation initiation factor 2 subunit 1 (eIF2α), Beclin-1 (Becn1), and Caspase-3 (Casp3); ER stress-related repair, including binding immunoglobulin protein [also known as 78 kDa glucose-regulated protein (BiP/GRP78)], protein disulfide isomerase (PDI), brain-derived neurotrophic factor (BDNF) and the inflammatory cytokine IL6, was assessed by western blotting of tibial nerves from rats in each age group. Expression of XBP1s and Becn1, which promote UPS and autophagy, decreased significantly after 50 weeks of age. However, expression of eIF2α and Casp3, which inhibit new protein biosynthesis and promote apoptosis, increased significantly after 50 weeks. Expression of BiP/GRP78 and PDI, which are refolding factors for denatured proteins, showed a significant decrease after 50 (or 70) weeks of age. The expression of BDNF, a ligand protein for the repair cascade, showed a significant increase after 70 weeks of age, while that of IL6 increased significantly after 50 weeks of age. These results indicate that ER stress-related degradation (UPS and autophagy) and refolding repair functions are reduced in rat tibial nerves after 50 weeks, followed by enhanced apoptosis and inflammation. These findings shed light on the progression of age-related peripheral neurodegeneration in rats.