Cytohesins, ARF GTP'ases and Neurodegeneration

摘要 神经退行性疾病如肌萎缩侧索硬化症的体外和体内模型 硬化症（ALS）提供了一个瞥见生物过程中出错， 这些紊乱。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积累、内质网应激、功能障碍 细胞内运输，兴奋性毒性，线粒体功能障碍，神经炎症，和 RNA加工异常GTP酶的ARF家族是一种遗传学上- 涉及膜运输，脂质代谢/信号传导， 肌动蛋白重塑和脂滴形成。根据这两起案件 ALS的病理生理学和ARF的一些生物学作用，我们想知道ARF是否 ALS的信号修饰模型。在最近发表的工作中，我们发现， 细胞粘连素（“Cy's”，ARF鸟嘌呤核苷酸交换因子）的活性是 神经保护了解这一观察结果的细胞生物学机制是 由于Cy和ARF的多效性作用，因此存在问题。前进的道路将 通过确定该过程中涉及的特定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， 将进行实验以确定单个Cy的抑制是否赋予 保护免受突变SOD或突变TDP 43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了一个或多个细胞的生长。 单个ARF赋予对突变的运动神经元的毒性作用的保护， SOD或突变体TDP 43。禁用时，特定Cy/ARF对的标识 神经保护将是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.