Cytohesins, ARF GTP'ases and Neurodegeneration

摘要 肌萎缩侧索硬化症等神经退行性疾病的体外和体内模型 肌萎缩侧索硬化症(ALS)让人们得以一窥在 这些障碍。目前的想法表明，主要的病理生理过程 包括蛋白质错误折叠和堆积、内质网应激、功能障碍 细胞内转运、兴奋性毒性、线粒体功能障碍、神经炎症和 异常的RNA处理。ARF家族的GTP酶是一个系统发育- 与膜运输、脂质代谢/信号转导有关的保守蛋白质家族， 肌动蛋白重塑和脂滴形成。基于两国之间的明显重叠 ALS的病理生理和ARF的一些生物学作用，我们想知道ARF是否 发出修改的ALS模型的信号。在最近发表的研究中，我们发现阻止 细胞粘附素(“Cy‘s”，ARF鸟核苷酸交换因子)的活性为 具有神经保护作用。理解这种观察的细胞生物学机制是 由于Cy和ARF的多效性作用，这是有问题的。前进的道路将是 通过确定此过程中涉及的特定Cy和特定ARF来促进 这将引导我们进入相关的细胞生物学过程。为此，在具体目标1中， 将进行实验以确定是否对单个Cy的抑制 抗突变型超氧化物歧化酶和突变型TDP43对运动神经元的毒性作用 在具体目标2中，将进行实验以确定是否抑制一种 个体ARF对突变型运动神经元的毒性作用具有保护作用 SOD或突变体TDP43。禁用时为的特定Cy/ARF对的标识 神经保护将成为深入了解机制和潜力的发射台 治疗靶向。

Abstract In vitro and in vivo models of neurodegenerative disease such as Amyotrophic Lateral Sclerosis (ALS) have provided glimpses into the biological processes that go awry in these disorders. Current thinking indicates that major pathophysiologic processes include protein misfolding and accumulation, endoplasmic reticulum stress, dysfunctional intracellular trafficking, excitotoxicity, mitochondrial dysfunction, neuroinflammation, and abnormal RNA processing. The ARF family of GTP'ases are a phylogenetically- conserved family of proteins involved with membrane traffic, lipid metabolism/signaling, actin remodeling, and lipid droplet formation. Based on the apparent overlap between ALS pathophysiology and some of the biological actions of ARFs, we wondered if ARF signaling modified models of ALS. In recently published work we find that blocking activity of cytohesins (“Cy's”, ARF guanine nucleotide exchange factors) is neuroprotective. Understanding the cell biological mechanism of this observation is problematic because of the pleiotropic actions of Cy's and ARFs. The path forward will be facilitated by determining the specific Cy and specific ARF involved in this process as this will guide us to the relevant cell biological process. To this end, in specific aim #1, experiments will be undertaken to determine if inhibition of an individual Cy confers protection against the toxic actions on motor neurons of mutant SOD or mutant TDP43. In specific aim #2, experiments will be undertaken to determine if inhibition of an individual ARF confers protection against the toxic actions on motor neurons of mutant SOD or mutant TDP43. Identification of the specific Cy/ARF pair that upon disabling is neuroprotective will be the launching pad for insight into mechanisms and potential therapeutic targeting.