Aberrant neurofilament phosphorylation in sensory neurons of rats with diabetic neuropathy
Aberrant neurofilament phosphorylation in sensory neurons of rats with diabetic neuropathy
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DOI：
10.2337/diabetes.48.4.881
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发表时间：
1999-04-01
期刊：
影响因子：
7.7
通讯作者：
Tomlinson, DR
中科院分区：
文献类型：
--
作者：
Fernyhough, P;Gallagher, A;Tomlinson, DR
神经丝的异常磷酸化存在于许多神经退行性疾病中，在本研究中，两种1型糖尿病的动物模型--自发性糖尿病BE大鼠和链脲佐菌素诱导的糖尿病大鼠--被用来确定这种现象是否与通常与糖尿病相关的对称性感觉性多神经病的病因有关。免疫细胞化学显示糖尿病大鼠腰背根神经节神经细丝磷酸化水平增加2~3倍(P<；0.001)，定位于中、大神经元核周；糖尿病使BE大鼠腓肠神经的神经细丝M磷酸化水平增加2.5倍(P<；0.05)。神经丝是丝裂原激活蛋白激酶(MAPK)家族的底物，该家族包括c-jun NH2末端激酶(JNK)或应激激活蛋白激酶(SAPK1)和细胞外信号调节激酶(ERKs)1和2。糖尿病引起DRG和腓肠神经中54 kDa JNK亚型的磷酸化显著增加三到四倍(P<；0.05)，这与c-jun和神经丝磷酸化水平升高有关，在糖尿病组，ERK磷酸化在DRG中也增加，但在腓肠神经中没有。免疫细胞化学显示JNK表达于糖尿病大鼠的感觉神经元核周和轴突中，运动神经元核周和腓神经中未见JNK的磷酸化。推测糖尿病大鼠感觉神经元中，神经丝的异常磷酸化可能参与了糖尿病大鼠远端感觉神经轴索病变的发生。
Aberrant neurofilament phosphorylation occurs in many neurodegenerative diseases, and in this study, two animal models of type 1 diabetes-the spontaneously diabetic BE 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 BE 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.