Pharmacology Institute, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
Molecular Physiology of Somatic Sensation, Department of Neuroscience, Max-Delbrück Centre for Molecular Medicine, Robert-Rössle Straße 10, 13092 Berlin, Germany.
Neuron. 2020 Sep 23;107(6):1141-1159.e7. doi: 10.1016/j.neuron.2020.06.037. Epub 2020 Jul 30.
Diabetic peripheral neuropathy (DPN) is a highly frequent and debilitating clinical complication of diabetes that lacks therapies. Cellular oxidative stress regulates post-translational modifications, including SUMOylation. Here, using unbiased screens, we identified key enzymes in metabolic pathways and ion channels as novel molecular targets of SUMOylation that critically regulated their activity. Sensory neurons of diabetic patients and diabetic mice demonstrated changes in the SUMOylation status of metabolic enzymes and ion channels. In support of this, profound metabolic dysfunction, accelerated neuropathology, and sensory loss were observed in diabetic gene-targeted mice selectively lacking the ability to SUMOylate proteins in peripheral sensory neurons. TRPV1 function was impaired by diabetes-induced de-SUMOylation as well as by metabolic imbalance elicited by de-SUMOylation of metabolic enzymes, facilitating diabetic sensory loss. Our results unexpectedly uncover an endogenous post-translational mechanism regulating diabetic neuropathy in patients and mouse models that protects against metabolic dysfunction, nerve damage, and altered sensory perception.
糖尿病周围神经病变（DPN）是糖尿病常见且严重的临床并发症，目前尚无有效的治疗方法。细胞氧化应激调节翻译后修饰，包括 SUMO 化。在这里，我们使用无偏筛选方法，鉴定了代谢途径和离子通道中的关键酶作为 SUMO 化的新型分子靶点，它们对其活性具有关键调控作用。糖尿病患者和糖尿病小鼠的感觉神经元表现出代谢酶和离子通道的 SUMO 化状态的改变。支持这一观点的是，在选择性缺乏外周感觉神经元中 SUMO 化蛋白能力的糖尿病基因靶向小鼠中，观察到明显的代谢功能障碍、加速的神经病理学和感觉丧失。糖尿病诱导的去 SUMO 化以及代谢酶去 SUMO 化引起的代谢失衡会损害 TRPV1 功能，从而促进糖尿病感觉丧失。我们的研究结果出人意料地揭示了一种内源性的翻译后调节机制，可保护患者和小鼠模型免受代谢功能障碍、神经损伤和感觉感知改变的影响，从而调节糖尿病神经病变。
