Metabolic Regulation of the Schwann Cell Injury Response

糖尿病周围神经病变是一种越来越常见的疾病，影响高达25%的糖尿病患者。糖尿病神经病变的病理基础是轴突完整性和功能的丧失。除了轴突损失外，损伤后神经纤维再生受损在糖尿病患者中很常见，在啮齿动物糖尿病模型中也得到了再现。轴突损伤触发受损轴突周围的雪旺细胞（SCs）发生戏剧性的重编程，最终形成“修复SC”表型。修复SC促进轴突/髓磷脂的分解和处理，吸引巨噬细胞，产生神经营养因子，并形成粘附分子。在与再生轴突接触后，它转变回分化的SC，以确保髓鞘再生或Remak束的形成。这种修复SC转变的主要调节因子是转录因子c-Jun，它在损伤后迅速激活

Diabetic peripheral neuropathy is an increasingly common disorder that affects up to 25% of diabetic patients. The pathological underpinning of diabetic neuropathy is the loss of axonal integrity and function. In addition to axonal loss, impaired nerve fiber regeneration after injury is commonplace in diabetics and is recapitulated in rodent diabetic models. Axonal injury triggers a dramatic reprogramming of the Schwann cells (SCs) surrounding the damaged axon that culminates in the adoption of a `repair SC' phenotype. The repair SC promotes axon/myelin breakdown and disposal, attracts macrophages, produces neurotrophic factors, and elaborates adhesive molecules. Upon contact with the regenerating axon, it transforms back into a differentiated SC to ensure remyelination or Remak bundle formation. The primary regulator of this repair SC transition is the transcription factor c-Jun, which is rapidly activated after injury in SCs surrounding damaged axons. In Jun-deficient mice, nerve regeneration is impaired. In keeping with the impaired axon regeneration in diabetes, we find that mice with mutations that alter SC metabolism fail to effectively promote nerve regeneration. Most recently, we characterized OGT-SCKO mice that lack SC expression of O-GlcNAc transferase (OGT), the enzyme that catalyzes addition of O-GlcNAc moieties to proteins at Ser and Thr residues. OGT activity is regulated by the flux of glucose through the hexosamine biosynthetic pathway, thus it serves as a sensor that aggregates information regarding glucose metabolism and transmits it into changes in cell physiology. Notably, abnormal O-GlcNAcylation has been implicated in diabetes, cancer, and neurodegenerative diseases. Mice lacking O-GlcNAcylation in SCs develop a tomaculous demyelinating neuropathy. Expression profiling of OGT-SCKO sciatic nerve revealed high expression of many AP-1 targets. Moreover, we find that JUN phosphorylation and transcriptional activity are regulated by O-GlcNAcylation. In keeping with abnormalities in JUN activity, we find that loss of OGT leads to a substantial decrease in regeneration/remyelination, indicating that the SC injury response is modulated by metabolism. These results lead us to hypothesize that poor nerve regeneration in diabetes, and potentially the neuropathy itself, is caused by the impact of abnormal metabolism on the generation, function, and/or cessation of the SC injury response. To pursue this hypothesis we propose three aims: 1) To investigate how metabolism impacts the SC injury response; 2) To investigate the role of O-GlcNAcylation in regulating JUN activity; and 3) To determine the role of AP-1 partners and other regulators in the SC injury response. Through these studies, we hope to show that therapies targeting Schwann cells and their repair functions will be useful in treating neuropathy and traumatic nerve injury.