B-cell lymphoma-extra large expression correlated with protein kinase RNA-like ER kinase and ubiquitination signals in the type 1 diabetes mouse model.

[INTRODUCTION] Diabetes mellitus with pain sensation is referred to as diabetic painful neuropathy (DN). DN development results from endoplasmic reticulum (ER) stress, including the upregulation of ER stress signaling-related molecules and autophagy. B-cell lymphoma-extra large (Bcl-), a protein of the antiapoptotic Bcl2 family, exhibits neuroprotective efficacy and expression profiles similar to those of protein kinase RNA-like ER kinase (PERK) in DN.

[OBJECTIVES] To investigate the roles of Bcl- in type 1 diabetes mellitus (T1DM).

[METHODS] This report used a single dose of streptozotocin (200 mg/kg) to establish a mouse model of T1DM, and to assay the changes in the expression profile of Bcl- and ER stress-related signal molecules with the dorsal root ganglia tissues.

[RESULTS] This study discovered the coexpression of Bcl- upregulation and PERK, a downstream mediator of ER stress (M1 Manders coefficients: 0.48-0.61, M2 Manders coefficients: 0.41-0.61). PERK phosphorylated eukaryotic initiation factor 2α (p-eIF2α) in the same sensory nociceptors (M1 Manders coefficients: 0.94-0.98, and M2 Manders coefficients: 0.97-0.98). This eIF2α upregulation was inversely correlated with thermal latencies ( = -0.89, < 0.0001) and mechanical thresholds ( = -0.75, < 0.0001). In addition to PERK upregulation, ubiquitin D (UBD), a key molecule in ubiquitination signaling, was upregulated and inversely correlated with neuropathic pain in DN.

[CONCLUSIONS] This study uncovers a new neuropathology underlying T1DM-associated DN: Bcl- activation associates PERK and ubiquitination marker upregulation in sensory neurons. Bcl- inactivation in nociceptors might be a potential target for relieving neuropathic pain of T1DM.