Investigating the Role of Atg1 in the Regulation of Glutamate Receptors

描述（由申请人提供）：中枢神经系统（CNS）中的化学传递依赖于神经元之间的有效通信。这一过程依赖于突触前末梢的空间正确形成和突触后受体的定位。谷氨酸能突触的发育和组装特别重要，因为中枢神经系统中的大部分兴奋性传递是通过离子型谷氨酸受体发生的。因此，谷氨酸受体（GluR）的功能或表达受损涉及几种神经病理学，包括某些形式的癫痫、中风/缺血、头部创伤、认知障碍和神经退行性疾病。因此，GluR的定位和贩运引起了人们的极大兴趣，但人们对它的了解仍然很少。最近的一项对果蝇神经肌肉接头处影响GluR簇形成的突变的正向遗传筛选显示，自噬特异性基因1（Atg 1）是谷氨酸受体（GluR）簇形成所必需的。atg 1是自噬所必需的，自噬是一种从细胞中去除细胞质和细胞器的保守过程。缺乏功能性atg 1基因的动物表现出GluR簇大小的显着减少。这种突变特异性地影响GluRs，因为在检查的其他突触蛋白中没有观察到差异。我们将研究atg 1的突变是否会改变GluR的转录或翻译，并确定atg 1是否会通过已知的调节细胞生长的途径来影响GluR簇的形成。通过分析atg 1突变体确定atg 1在GluR簇形成中的作用，将提高我们对自噬、自噬和GluR表达和定位机制的理解。公共卫生相关性：大脑细胞之间的大部分交流利用神经递质谷氨酸盐。谷氨酸受体聚集在谷氨酸释放区域附近的细胞中。谷氨酸受体的功能或表达受损涉及几种神经病理学，包括某些形式的癫痫、中风/缺血、头部创伤、认知障碍和神经退行性疾病。因此，谷氨酸受体的表达和定位是相当感兴趣的，但仍然知之甚少。使用遗传技术，我们确定了自噬特异性基因1（Atg 1）的突变导致细胞中谷氨酸受体数量的显着减少。在这个项目中，我们将研究Atg 1影响谷氨酸受体的机制。通过分析atg 1突变体来确定atg 1在谷氨酸受体簇形成中的作用，将提高我们对自噬和谷氨酸受体表达和定位机制的理解。

DESCRIPTION (provided by applicant): Chemical transmission in the central nervous system (CNS) relies on effective communication between neurons. This process is dependent upon the spatially correct formation of presynaptic terminals and the localization of postsynaptic receptors. The development and assembly of glutamatergic synapses is of particular importance because the majority of excitatory transmission in the CNS occurs via ionotropic glutamate receptors. As such, impaired function or expression of glutamate receptors (GluRs) is implicated in several neuropathologies including certain forms of epilepsy, stroke/ischemia, head trauma, cognitive impairments, and neurodegenerative disease. Therefore, the targeting and trafficking of GluRs is of considerable interest but remains poorly understood. A recent forward genetic screen for mutations that affect GluR cluster formation at the Drosophila neuromuscular junction revealed that the autophagy-specific gene 1 (Atg1) is necessary for the formation of glutamate receptor (GluR) clusters. Atg1 is required for autophagy, a well-conserved process that removes cytoplasm and organelles from cells. Animals lacking a functional atg1 gene exhibit a significant reduction in GluR cluster size. This mutation specifically affects GluRs as there is no observed difference in other synaptic proteins examined. We will investigate whether mutations in atg1 alter the transcription or translation of GluRs and determine whether atg1 affects GluR cluster formation by signaling through known pathways that regulate cell growth. Determining the role of atg1 in GluR cluster formation by analyses of atg1 mutants will improve our understanding of both autophagy both autophagy and the mechanisms that govern GluR expression and localization. PUBLIC HEALTH RELEVANCE: The majority of communication between the cells of the brain utilizes the neurotransmitter glutamate. Glutamate receptors cluster in cells adjacent to areas where glutamate is released. Impaired function or expression of glutamate receptors is implicated in several neuropathologies including certain forms of epilepsy, stroke/ischemia, head trauma, cognitive impairments, and neurodegenerative disease. Therefore, the expression and localization of glutamate receptors is of considerable interest but remains poorly understood. Using genetic techniques, we determined mutations of the autophagy-specific gene 1 (Atg1) cause a significant reduction in number of glutamate receptors in cells. For this project, we will investigate the mechanism(s) by which Atg1 affects glutamate receptors. Determining the role of atg1 in glutamate receptor cluster formation by analyses of atg1 mutants will improve our understanding of both autophagy and the mechanisms that govern glutamate receptor expression and location.