O-GlcNAcylation of tau: a link between glucose metabolism and neurodegeneration

脑内tau蛋白的异常过度磷酸化和聚集是神经退行性变的关键 阿尔茨海默病（AD）。葡萄糖摄取/代谢在AD脑中受损，这被认为是导致AD的原因。 神经变性然而，这种损伤如何导致神经退行性变尚不清楚。的 该项目的具体目标是揭示tau O-GlcNAc化的性质和功能作用[一种独特的类型 β-N-乙酰葡糖胺（GlcNAc）通过O-糖基化连接到丝氨酸或苏氨酸残基， 蛋白质]并揭示AD脑葡萄糖摄取/代谢受损的机制 会导致神经退化本建议的长期目标是了解该机制 AD中神经退行性变的研究，并在此基础上，制定预防和治疗AD的策略， 疾病因此，具体的目的是：（1）定位tau的O-GlcNAc化位点，并确定tau蛋白的变化。 AD脑中的tau O-GlcNAc化。tau O-GlcNAc化变化的根本原因也将是 通过比较脑内UDP-GlcNAc水平、O-GlcNAc转移酶和O-GlcNAc酶活性， AD和对照组之间的差异(2)研究tau蛋白的O-GlcNAc酰化和磷酸化之间的相互作用 无论是在体外还是在分化的PC 12细胞中。tau O-GlcNAc酰化的功能作用将通过以下方法进行研究： 测量其微管结合和组装活性并检查细胞形态和细胞器 改变tau O-GlcNAc酰化后的转运。(3)研究受损的分子机制 脑葡萄糖摄取/代谢有助于AD的神经变性。两种受损动物模型 脑葡萄糖摄取/代谢：禁食小鼠和脑室内注射 细胞松弛素B将用于研究其对tau O-GlcNAc酰化和磷酸化的作用。的确切作用 O-GlcNAc在低糖诱导的tau蛋白过度磷酸化和神经退行性变中的作用 还将在小鼠脑中阐明摄取/代谢。这些研究将揭示自然和 tau O-GlcNAc化及其在AD脑中的失调的功能作用，并通过以下方法揭示其机制： AD的脑葡萄糖摄取/代谢受损导致神经变性。完成 这些研究将为AD的神经退行性变机制提供新的见解， 预防和治疗AD以及可能的其他神经退行性疾病的新策略。

Abnormal hyperphosphorylation and aggregation of tau protein in the brain are critical to neurodegeneration of Alzheimer diesease (AD). Glucose uptake/metabolism is impaired in AD brain, which is believed to cause neurodegeneration. However, how this impairment contributes to neurodegeneration is unknown. The specific goal of this project is to reveal the nature and functional role of tau O-GlcNAcylation [a unique type of O-glycosylation by which beta-N-acetylglucosamine (GlcNAc) is linked to serine or threonine residues of proteins] and to uncover the mechanism by which impaired brain glucose uptake/metabolism of AD contributes to neurodegeneration. The long-term objective of this proposal is to understand the mechanism of neurodegeneration in AD and, based on this knowledge, to develop strategies to prevent and treat the disease. Hence, the specific aims are: (1) Map the O-GlcNAcylation sites of tau and determine the change of tau O-GlcNAcylation in AD brain. The underlying cause of the change in tau O-GlcNAcylation will also be studied by comparing brain level of UDP-GlcNAc and activities of O-GlcNAc transferase and O-GlcNAcase between AD and controls. (2) Study the interactions between O-GlcNAcylation and phosphorylation of tau both in vitro and in differentiated PC12 cells. The functional role of tau O-GlcNAcylation will be studied by measuring its microtubule-binding and -assembly activities and examining cell morphology and organelle transport upon alteration of tau O-GlcNAcylation. (3) Investigate the molecular mechanism by which impaired brain glucose uptake/metabolism contributes to neurodegeneration of AD. Two animal models of impaired brain glucose uptake/metabolism¿fasted mice and mice after intracerebroventricular injection of cytochalasin B¿will be used to study its effects on tau O-GlcNAcylation and phosphorylation. The exact role of O-GlcNAcylation in tau hyperphosphorylation and neurodegeneration induced by low glucose uptake/metabolism will also be elucidated in the mouse brains. These studies will reveal the nature and functional role of tau O-GlcNAcylation and its dysregulation in AD brain and uncover the mechanism by which impaired brain glucose uptake/metabolism of AD contributes to neurodegeneration. Completion of these studies will provide new insight into the mechanism of neurodegeneration of AD and help develop novel strategies to prevent and treat AD and probably other neurodegenerative disorders.