Institute of Pharmacology, Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
Centre for Organismal Studies (COS), University of Heidelberg, Im Neuenheimer Feld 360, 69120 Heidelberg, Germany.
Cells. 2023 Oct 24;12(21):2511. doi: 10.3390/cells12212511.
Diabetic peripheral neuropathy (DPN) is the prevalent type of peripheral neuropathy; it primarily impacts extremity nerves. Its multifaceted nature makes the molecular mechanisms of diabetic neuropathy intricate and incompletely elucidated. Several types of post-translational modifications (PTMs) have been implicated in the development and progression of DPN, including phosphorylation, glycation, acetylation and SUMOylation. SUMOylation involves the covalent attachment of small ubiquitin-like modifier (SUMO) proteins to target proteins, and it plays a role in various cellular processes, including protein localization, stability, and function. While the specific relationship between high blood glucose and SUMOylation is not extensively studied, recent evidence implies its involvement in the development of DPN in type 1 diabetes. In this study, we investigated the impact of SUMOylation on the onset and progression of DPN in a type 2 diabetes model using genetically modified mutant mice lacking SUMOylation, specifically in peripheral sensory neurons (SNS-Ubc9). Behavioural measurement for evoked pain, morphological analyses of nerve fibre loss in the epidermis, measurement of reactive oxygen species (ROS) levels, and antioxidant molecules were analysed over several months in SUMOylation-deficient and control mice. Our longitudinal analysis at 30 weeks post-high-fat diet revealed that SNS-Ubc9 mice exhibited earlier and more pronounced thermal and mechanical sensation loss and accelerated intraepidermal nerve fibre loss compared to control mice. Mechanistically, these changes are associated with increased levels of ROS both in sensory neuronal soma and in peripheral axonal nerve endings in SNS-Ubc9 mice. In addition, we observed compromised detoxifying potential, impaired respiratory chain complexes, and reduced levels of protective lipids in sensory neurons upon deletion of SUMOylation in diabetic mice. Importantly, we also identified mitochondrial malate dehydrogenase (MDH2) as a SUMOylation target, the activity of which is negatively regulated by SUMOylation. Our results indicate that SUMOylation is an essential neuroprotective mechanism in sensory neurons in type 2 diabetes, the deletion of which causes oxidative stress and an impaired respiratory chain, resulting in energy depletion and subsequent damage to sensory neurons.
糖尿病周围神经病变（DPN）是最常见的周围神经病变类型；它主要影响四肢神经。其多方面的性质使得糖尿病神经病变的分子机制复杂且不完全阐明。几种类型的翻译后修饰（PTMs）已被牵连到 DPN 的发展和进展中，包括磷酸化、糖化、乙酰化和 SUMO 化。SUMO 化涉及小泛素样修饰物（SUMO）蛋白与靶蛋白的共价连接，它在包括蛋白质定位、稳定性和功能在内的各种细胞过程中发挥作用。虽然高血糖与 SUMO 化之间的具体关系尚未广泛研究，但最近的证据表明其参与了 1 型糖尿病中 DPN 的发展。在这项研究中，我们使用缺乏 SUMO 化的遗传修饰突变小鼠（特别是在外周感觉神经元（SNS-Ubc9）中）研究了 SUMO 化对 2 型糖尿病模型中 DPN 的发病和进展的影响。我们在 SUMO 化缺陷和对照小鼠中分析了几个月的诱发疼痛行为测量、表皮神经纤维丢失的形态分析、活性氧（ROS）水平和抗氧化分子的测量。我们在高脂肪饮食后 30 周的纵向分析表明，与对照小鼠相比，SNS-Ubc9 小鼠表现出更早和更明显的热和机械感觉丧失以及加速的表皮内神经纤维丢失。从机制上讲，这些变化与 SNS-Ubc9 小鼠感觉神经元体和周围轴突神经末梢中 ROS 水平的增加有关。此外，我们观察到在糖尿病小鼠中删除 SUMO 化后，感觉神经元中的解毒潜力受损、呼吸链复合物受损以及保护性脂质水平降低。重要的是，我们还鉴定出线粒体苹果酸脱氢酶（MDH2）作为 SUMO 化的靶标，其活性受到 SUMO 化的负调控。我们的结果表明，SUMO 化是 2 型糖尿病中感觉神经元的一种重要神经保护机制，其缺失会导致氧化应激和呼吸链受损，导致能量耗竭，随后感觉神经元受损。
