Impaired slow axonal transport in diabetic peripheral nerve is independent of RAGE
Impaired slow axonal transport in diabetic peripheral nerve is independent of RAGE
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DOI：
10.1111/ejn.12333
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发表时间：
2013-10-01
影响因子：
3.4
通讯作者：
Schmidt, Ann Marie
中科院分区：
文献类型：
--
作者：
Juranek, Judyta K.;Geddis, Matthew S.;Schmidt, Ann Marie
糖尿病周围神经功能障碍是30-50%长期糖尿病患者常见的并发症。这种功能障碍的发病机制尚不清楚，但越来越多的证据表明，它可能部分归因于轴突运输的改变。我们之前的研究表明，RAGE（高级糖基化终产物受体）会导致糖尿病周围神经病变的发病机制，并损害坐骨神经挤压后的神经再生，特别是在糖尿病中。我们假设 RAGE 通过其细胞质结构域与哺乳动物 Diaphanous 1 (mDia1) - 肌动蛋白相互作用分子的相互作用在轴突运输损伤中发挥作用。研究表明，mDia1-RAGE 相互作用对于 RAGE 配体依赖性细胞迁移、AKT 磷酸化、巨噬细胞炎症反应和平滑肌迁移是必需的。在这里，我们研究了坐骨神经挤压后 1、3 和 6 小时野生型 C57BL/6 和 RAGE 无效对照以及注射链脲佐菌素的糖尿病小鼠的周围神经中的 RAGE、mDia1 和轴突转运率标记物。结果显示，在对照神经和糖尿病神经中，挤压区域近端和远端积累的RAGE量相似，表明RAGE的再循环率非常高，并且它均匀地往返于神经元细胞体。此外，我们发现蛋白质（例如神经丝）的缓慢轴突运输以不依赖于 RAGE 的方式受到糖尿病的影响。最后，我们的研究表明 mDia1 轴突运输在糖尿病中受损，这表明影响肌动蛋白结合蛋白的糖尿病相关变化发生在病程早期。
Diabetic peripheral nerve dysfunction is a common complication occurring in 30-50% of long-term diabetic patients. The pathogenesis of this dysfunction remains unclear but growing evidence suggests that it might be attributed, in part, to alteration in axonal transport. Our previous studies demonstrated that RAGE (Receptor for Advanced Glycation Endproducts) contributes to the pathogenesis of diabetic peripheral neuropathy and impairs nerve regeneration consequent to sciatic nerve crush, particularly in diabetes. We hypothesize that RAGE plays a role in axonal transport impairment via the interaction of its cytoplasmic domain with mammalian Diaphanous 1 (mDia1) - actin interacting molecule. Studies showed that mDia1-RAGE interaction is necessary for RAGE-ligand-dependent cellular migration, AKT phosphorylation, macrophage inflammatory response and smooth muscle migration. Here, we studied RAGE, mDia1 and markers of axonal transport rates in the peripheral nerves of wild-type C57BL/6 and RAGE null control and streptozotocin-injected diabetic mice at 1, 3 and 6h after sciatic nerve crush. The results show that in both control and diabetic nerves, the amount of RAGE accumulated at the proximal and distal side of the crush area is similar, indicating that the recycling rate for RAGE is very high and that it is evenly transported from and towards the neuronal cell body. Furthermore, we show that slow axonal transport of proteins such as Neurofilament is affected by diabetes in a RAGE-independent manner. Finally, our study demonstrates that mDia1 axonal transport is impaired in diabetes, suggesting that diabetes-related changes affecting actin binding proteins occur early in the course of the disease.