Creatine Transporter Deficiency and Brain Energetics

项目总结(说明) 肌酸(Cr)及其高能产物磷酸肌酸(Pcr)是磷酸原的关键成分 与糖酵解一起补充三磷酸腺苷，为细胞正常功能提供燃料的系统。这个 人体利用精氨酸和甘氨酸合成每日所需铬的大约50% 精氨酸：甘氨酸氨基转移酶(AGAT，肾脏)和乙酸胍甲基转移酶(GAMT，in 肝脏)，另一半的铬来自食物。虽然它的亚细胞定位尚不清楚，但肌酸 转运蛋白(CRT)对于建立/维持人类大脑中的铬浓度是必不可少的，这显然是 在2001年首次发现的CRT缺乏症中表现出来。在没有CRT(即 位于X染色体上)，患此病的儿童表现出严重的认知缺陷和接近完全 磁共振波谱(MRS)缺乏脑铬/聚合酶链式反应。重要的是，与肌萎缩侧索硬化症患者不同 合成酶突变，CRT缺乏者对补铬反应差。因此， 有必要确定CRT的功能及其缺陷的神经病理基础，以便 开发有效的临床治疗方法。 根据这些结果，我们推测，缺乏铬/聚合酶促进了AMPK和自噬 信号通路，同时抑制脑中mTOR活性，导致树突棘发育不全和 对缺氧缺血性损伤的易感性。此外，CRT介导铬跨周细胞和/或细胞的转运。 星形胶质细胞末端位于大脑中。最后，鼻腔应用铬可恢复脑内铬/聚合酶原水平并纠正 CRT缺乏的神经病理后果。我们将在三个具体目标上检验这些假设。 目的1：确定CRT在脑内的功能和亚细胞定位。 目的：探讨CRT缺陷对细胞信号转导和脑缺血的影响。 目的3：研究CRT缺乏症的神经病理和认知功能障碍的治疗方法。

PROJECT SUMMARY (Description) Creatine (Cr) and its high-energy product phosphocreatine (PCr) are key components of the phosphagen system that, along with glycolysis, replenishes ATP to provide the fuels for proper cellular functions. The human body synthesizes approximately 50% of the daily need for Cr from arginine and glycine using arginine:glycine amidinotrasnferase (AGAT, in kidney) and guanidinoacetate methyltransferase (GAMT, in liver), and the other half of Cr is derived from food. While its subcellular localization remains unclear, creatine transporter (CrT) is essential for building/maintaining the brain Cr concentration in humans, which is clearly demonstrated in the disease CrT deficiency that was first discovered in 2001. In the absence of CrT (which is located in the X-chromosome), the afflicted children manifest severe cognitive deficits and near-complete absence of the brain Cr/PCr on magnetic resonance spectroscopy (MRS). Importantly, unlike patients with Cr synthesis enzyme mutations, those with CrT deficiency respond poorly to Cr supplement treatment. Hence, there is a need to determine the functions of CrT and the neuropathological basis of its deficiency in order to develop effective clinical treatments. Based on these results, we hypothesize that the absence of Cr/PCr promotes the AMPK and autophagic signaling pathways, while suppressing mTOR activity in the brain, leading to dendritic spine dysgenesis and susceptibility to hypoxic-ischemic injury. Further, CrT mediates the transport of Cr across pericytes and/or the astroglial end-feet in the brain. Finally, intranasal Cr application can restore the brain Cr/PCr level and correct neuropathological consequences of CrT deficiency. We will test these hypotheses in three specific aims. Aim 1: To determine the functions and sub-cellular location of CrT in the brain. Aim 2: To determine the impacts of CrT deficiency on cell signaling and cerebral ischemia. Aim 3: To develop treatments of the neuropathological and cognitive deficits in CrT deficiency.