PERK determines polarized targeting of growth factors in neurons

摘要 内质网应激感受器PERK通常用于减弱蛋白质合成和激活细胞凋亡途径。 因此，将PERK与阿尔茨海默氏症和肥胖症联系起来的大部分工作都集中在操纵这一点上 活动。然而，与神经退行性变风险增加相关的PERK基因变异 最近被证明降低了激酶的活性，这表明PERK通路也具有重要的 可能具有神经保护作用的适应性功能。操纵这些保护功能同样重要 神经退行性变。我们发现了PERK的一个这样的功能，它是正确本地化的基础 生长因子到轴突和树突，这反过来又是它们局部分泌和 神经保护。PERK参与了生长因子的定位，因为它在小鼠皮质中的缺失 神经元或蠕虫化学感觉神经元取消正确的轴突/树突分布，并抑制 胰岛素样生长因子和转化生长因子β的分泌。这项建议探讨了PERK如何控制轴突/树突的定位。 和分泌这些神经保护性生长因子。 在目标1中，我们将确定PERK的激酶活性是否是生长因子在神经元中定位所必需的， 它的主要磷酸化底物eif2α是否介导这一活性，以及PERK是否存在危险等位基因 与神经退行性变相关，改变生长因子的分布。在目标2中，我们将继续遗传 数据表明，生长因子定位的PERK调节依赖于钙的成分 动态平衡机制，既包括膜通道，也包括胞浆介质。在这两个目标上，我们将结合起来 用生化分析对蠕虫和小鼠感觉神经元的遗传分析，因为 这些方法提供了互补的见解。 该项目将确定一种新的细胞途径，它是生长因子极化分泌的基础，通过 神经元，因此它们的功能连接。了解PERK如何执行这一新的保护 神经元的功能将开启在症状前AD和自闭症中操纵这些通路的选择 模型，并描述致敏和保护机制。

Abstract The ER stress sensor PERK usually serves to attenuate protein synthesis and activate apoptotic pathways. Thus, most of the work linking PERK to Alzheimer's disease and to tauophathies focuses on manipulating this activity. However, the genetic variants of PERK associated with increased risk for neurodegeneration have recently been shown to have reduced kinase activity, suggesting that the PERK pathway also has important adaptive functions that may be neuro-protective. Manipulating these protective functions is equally important for neurodegeneration. We discovered one such function of PERK, which underlies the proper localization of growth factors to axons and dendrites, which in turn is a pre-requisite for their local secretion and neuroprotection. PERK is involved in growth factor localization because its deletion in either mouse cortical neurons or in worm chemosensory neurons abolishes the correct axonal/dendritic distribution and inhibits the secretion of IGFs and TGFβ. This proposal explores how PERK controls axonal/dendritic localization and secretion of these neuroprotective growth factors. In Aim 1 we will determine if the kinase activity of PERK is necessary for growth factor localization in neurons, whether its main phosphorylation substrate, eIF2α, mediates this activity, and whether the PERK risk alleles associated with neurodegeneration alter the distribution of growth factors. In Aim 2 we will follow on genetic data indicating that PERK regulation of growth factor localization depends on components of the calcium homeostasis machinery, both membrane channels and cytosolic mediators. In both Aims we will combine genetic analyses of sensory neurons in worms and mice with biochemical analyses, because of the complementary insights provided by these approaches. This project will identify a novel cellular pathway that underlies the polarized secretion of growth factor by neurons and thus their functional connectivity. Understanding how PERK performs this novel protective function in neurons will open options of manipulating these pathways in presymptomatic AD and tauopathy models, and into delineating sensitizing vs protective mechanisms.