Investigating the Role of Atg1 in the Regulation of Glutamate Receptors

描述(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沟通。这个过程依赖于突触前终末在空间上的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尤为重要，因为中枢神经系统的兴奋性传递大部分是通过离子型谷氨酸受体进行的。因此，谷氨酸受体(GluRs)的功能或表达受损与多种神经病理有关，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，针对GluRs和贩运GluRs引起了相当大的兴趣，但仍然知之甚少。最近对影响果蝇神经肌肉接头处GluR簇形成的突变进行的正向遗传筛查显示，自噬特异基因1(Atg1)是形成谷氨酸受体(GluR)簇所必需的。ATG1是自噬所必需的，这是一种保守的过程，可以将细胞质和细胞器从细胞中移除。缺乏功能性ATg1基因的动物表现出GluR簇大小的显著减少。这种突变特别影响GluRs，因为在所检测的其他突触蛋白中没有观察到差异。我们将研究Atg1的突变是否会改变GluR的转录或翻译，并确定Atg1是否通过调节细胞生长的已知途径影响GluR簇的形成。通过对Atg1突变体的分析来确定Atg1在GluR簇形成中的作用，将有助于我们对自噬以及控制GluR表达和定位的机制的理解。与公共健康相关：脑细胞之间的大部分交流利用神经递质谷氨酸。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与多种神经病理有关，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引起了人们的极大兴趣，但仍知之甚少。利用基因技术，我们确定自噬特异基因1(Atg1)的突变会导致细胞中谷氨酸受体数量的显著减少。在这个项目中，我们将研究ATG1影响谷氨酸受体的机制(S)。通过对Atg1突变体的分析，确定Atg1在谷氨酸受体簇形成中的作用，将有助于我们更好地理解自噬以及控制谷氨酸受体表达和定位的机制。

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.