Aberrant neurofilament phosphorylation in sensory neurons of rats with diabetic neuropathy.
Aberrant neurofilament phosphorylation occurs in many neurodegenerative diseases, and in this study, two animal models of type 1 diabetes--the spontaneously diabetic BB rat and the streptozocin-induced diabetic rat--have been used to determine whether such a phenomenon is involved in the etiology of the symmetrical sensory polyneuropathy commonly associated with diabetes. There was a two- to threefold (P < 0.05) elevation of neurofilament phosphorylation in lumbar dorsal root ganglia (DRG) of diabetic rats that was localized to perikarya of medium to large neurons using immunocytochemistry. Additionally, diabetes enhanced neurofilament M phosphorylation by 2.5-fold (P < 0.001) in sural nerve of BB rats. Neurofilaments are substrates of the mitogen-activated protein kinase (MAPK) family, which includes c-jun NH2-terminal kinase (JNK) or stress-activated protein kinase (SAPK1) and extracellular signal-regulated kinases (ERKs) 1 and 2. Diabetes induced a significant three- to fourfold (P < 0.05) increase in phosphorylation of a 54-kDa isoform of JNK in DRG and sural nerve, and this correlated with elevated c-Jun and neurofilament phosphorylation. In diabetes, ERK phosphorylation was also increased in the DRG, but not in sural nerve. Immunocytochemistry showed that JNK was present in sensory neuron perikarya and axons. Motoneuron perikarya and peroneal nerve of diabetic rats showed no evidence of increased neurofilament phosphorylation and failed to exhibit phosphorylation of JNK. It is hypothesized that in sensory neurons of diabetic rats, aberrant phosphorylation of neurofilament may contribute to the distal sensory axonopathy observed in diabetes.
Fernyhough
P
P
Division of Neuroscience, School of Biological Sciences, University of Manchester, UK. paul.fernyhough@man.ac.uk
Gallagher
A
A
Averill
S A
SA
Priestley
J V
JV
Hounsom
L
L
Patel
J
J
Tomlinson
D R
DR
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases; D008161:Lumbosacral Region; D008297:Male; D020928:Mitogen-Activated Protein Kinases; D009046:Motor Neurons / Q000378:metabolism; D009431:Neural Conduction / Q000502:physiology; D016900:Neurofilament Proteins / Q000378:metabolism*; D009475:Neurons, Afferent / Q000378:metabolism* / Q000502:physiology; D010543:Peroneal Nerve / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D011913:Rats, Inbred BB / Q000235:genetics; D017208:Rats, Wistar; D013497:Sural Nerve / Q000378:metabolism / Q000473:pathology
D016900:Neurofilament Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases