Upregulation of Vesicular Glutamate Transporter 2 and STAT3 Activation in the Spinal Cord of Mice Receiving 3,3′-Iminodipropionitrile
Upregulation of Vesicular Glutamate Transporter 2 and STAT3 Activation in the Spinal Cord of Mice Receiving 3,3′-Iminodipropionitrile
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DOI：
10.1007/s12640-017-9822-x
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发表时间：
2017-09
影响因子：
3.7
通讯作者：
T. Ohgomori;R. Yamasaki;J. Kira;S. Jinno
中科院分区：
文献类型：
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作者：
T. Ohgomori;R. Yamasaki;J. Kira;S. Jinno
长期给予3，3 ′-亚氨基二丙腈（IDPN）可引起轴突损伤。尽管仍存在争议，但有人认为IDPN中毒与肌萎缩侧索硬化症（ALS）的轴突病变相似。有趣的是，最近的研究，包括我们自己的研究表明，在IDPN处理的小鼠和家族性ALS的遗传模型SOD 1G 93 Amice中，脊髓α运动神经元中的信号转导和转录激活因子3（STAT 3）被激活。由于STAT 3的激活发生在对各种刺激的反应中，如轴突损伤、缺血和过量的谷氨酸，因此我们在此集中研究了IDPN处理的小鼠和SOD 1G 93 Amice中磷酸化STAT 3（pSTAT 3，一种活性形式）和囊泡谷氨酸转运蛋白2（VGluT 2，谷氨酸储存和释放的调节剂）之间的潜在联系。通过蛋白质印迹分析证实轴突运输受损：磷酸化神经丝H的表达水平在两种模型中均升高。如SOD 1G 93 Amice所示，IDPN处理小鼠脊髓α运动神经元周围突触素阳性（SYP）+突触前末梢中VGluT 2的表达频率显著高于溶剂对照组。在IDPN处理的小鼠和SOD 1G 93 Amice中，VGluT 2+突触前末梢对脊髓α运动神经元的覆盖率在pSTAT 3+细胞周围比在pSTAT 3 −细胞周围更高。考虑到过量的谷氨酸被证明参与轴突损伤和STAT 3激活，本研究结果表明，IDPN诱导的VGluT 2上调可能导致谷氨酸的增加，这可能导致轴突病和pSTAT 3的诱导。VGluT 2的上调和STAT 3通过谷氨酸的激活之间的联系可能代表了IDPN处理的小鼠和SOD 1G 93 Amice的共同病理特征。
Chronic administration of 3,3′-iminodipropionitrile (IDPN) causes axonal impairment. Although controversy still remains, it has been suggested that IDPN intoxication mimics the axonopathy of amyotrophic lateral sclerosis (ALS). Interestingly, recent studies including our own showed that signal transducer and activator of transcription 3 (STAT3) in spinal α-motoneurons was activated in both IDPN-treated mice andSOD1G93Amice, a genetic model of familial ALS. Because activation of STAT3 occurs in response to various stimuli, such as axonal injury, ischemia, and excessive glutamate, here we focused on a potential link between phosphorylated STAT3 (pSTAT3, an active form) and vesicular glutamate transporter 2 (VGluT2, a regulator of glutamate storage and release) in IDPN-treated mice andSOD1G93Amice. Impairment of axonal transport was confirmed by western blot analysis: the expression levels of phosphorylated neurofilament H were elevated in both models. As shown inSOD1G93Amice, the expression frequencies of VGluT2 in synaptophysin-positive (SYP)+presynaptic terminals around spinal α-motoneurons were significantly higher in IDPN-treated mice than in vehicle controls. The coverages of spinal α-motoneurons by VGluT2+presynaptic terminals were more elevated around pSTAT3+cells than around pSTAT3−cells in IDPN-treated mice andSOD1G93Amice. Considering that excessive glutamate is shown to be involved in axonal impairment and STAT3 activation, the present results suggest that IDPN-induced upregulation of VGluT2 may result in an increase in glutamate, which might cause axonopathy and induction of pSTAT3. The link between upregulation of VGluT2 and activation of STAT3 via glutamate may represent a common pathological feature of IDPN-treated mice andSOD1G93Amice.