Aberrant neurofilament phosphorylation in sensory neurons of rats with diabetic neuropathy

Aberrant neurofilament phosphorylation occurs in many neurodegenerative dis eases, and in this study, two animal models of type 1 diabetes-the spontane ously diabetic BE rat and the streptozocin-induced diabetic rat-have been u sed to determine whether such a phenomenon is involved in the etiology of t he symmetrical sensory polyneuropathy commonly associated with diabetes. Th ere was a two- to threefold (P < 0.05) elevation of neurofilament phosphory lation in lumbar dorsal root ganglia (DRG) of diabetic rats that was locali zed to perikarya of medium to large neurons using immunocytochemistry, Addi tionally, diabetes enhanced neurofilament M phosphorylation by 2.5-fold (P < 0.001) in sural nerve of BE rats. Neurofilaments are substrates of the mi togen-activated protein kinase (MAPK) family, which includes c-jun NH2-term inal kinase (JNK) or stress-activated protein kinase (SAPK1) and extracellu lar signal-regulated kinases (ERKs) 1 and 2, Diabetes induced a significant three- to fourfold (P < 0.05) increase in phosphorylation of a 54-kDa isof orm of JNK in DRG and sural nerve, and this correlated with elevated c-Jun and neurofilament phosphorylation, In diabetes, ERK phosphorylation was als o increased in the DRG, but not in sural nerve. Immunocytochemistry showed that JNK was present in sensory neuron perikarya and axons, Motoneuron peri karya and peroneal nerve of diabetic rats showed no evidence of increased n eurofilament phosphorylation and failed to exhibit phosphorylation of JNK, It is hypothesized that in sensory neurons of diabetic rats, aberrant phosp horylation of neurofilament may contribute to the distal sensory axonopathy observed in diabetes.