Jones James I, Costa Christopher J, Cooney Caitlin, Goldberg David C, Ponticiello Matthew, Cohen Melanie W, Mellado Wilfredo, Ma Thong C, Willis Dianna E
Burke Neurological Institute, White Plains, NY, United States.
Feil Family Brain & Mind Research Institute, Weill Cornell Medicine, New York, NY, United States.
Front Mol Neurosci. 2021 Dec 7;14:728163. doi: 10.3389/fnmol.2021.728163. eCollection 2021.
Most diabetes patients eventually suffer from peripheral nerve degeneration. Unfortunately, there is no treatment for the condition and its mechanisms are not well understood. There is, however, an emerging consensus that the inability of peripheral nerves to regenerate normally after injury contributes to the pathophysiology. We have previously shown that regeneration of peripheral axons requires local axonal translation of a pool of axonal mRNAs and that the levels and members of this axonal mRNA pool are altered in response to injury. Here, we show that following sciatic nerve injury in a streptozotocin rodent model of type I diabetes, this mobilization of RNAs into the injured axons is attenuated and correlates with decreased axonal regeneration. This failure of axonal RNA localization results from decreased levels of the RNA binding protein ZBP1. Over-expression of ZBP1 rescues the growth defect in injured dorsal root ganglion neurons from diabetic rodents. These results provide evidence that decreased neuronal responsiveness to injury in diabetes is due to a decreased ability to alter the pool of axonal mRNAs available for local translation, and may open new therapeutic opportunities for diabetic peripheral neuropathy.
大多数糖尿病患者最终会患上周围神经变性。不幸的是，这种疾病尚无治疗方法，其发病机制也未得到充分了解。然而，目前已逐渐形成一种共识，即周围神经在损伤后无法正常再生是导致其病理生理过程的原因之一。我们之前已经表明，周围轴突的再生需要一组轴突mRNA进行局部轴突翻译，并且该轴突mRNA池的水平和组成成员会因损伤而发生改变。在此，我们发现，在链脲佐菌素诱导的I型糖尿病啮齿动物模型中，坐骨神经损伤后，RNA向损伤轴突的这种动员作用减弱，并且与轴突再生减少相关。轴突RNA定位失败是由于RNA结合蛋白ZBP1水平降低所致。ZBP1的过表达可挽救糖尿病啮齿动物受损背根神经节神经元的生长缺陷。这些结果表明，糖尿病中神经元对损伤的反应性降低是由于改变可用于局部翻译的轴突mRNA池的能力下降所致，这可能为糖尿病周围神经病变带来新的治疗机会。
