PERK determines polarized targeting of growth factors in neurons

摘要： 这一竞争性修订将扩大原来的赠款“津贴决定两极化的目标增长因素 神经元中”（1 R21 AG 063029），探索阿尔茨海默病相关基因中的人类遗传变异如何， 包括PERK，影响神经元对SARS-CoV-2感染的敏感性。大量AD/tau蛋白病 基因或者有助于细胞的分泌功能（当为野生型时），或者破坏它并引起ER应激， 翻译沉默（当突变或受损时）。另一方面，冠状病毒破坏宿主细胞ER 和翻译机器来产生它们自己的蛋白质。因此，影响这些途径的AD等位基因是 这里假设也影响新型SARS-CoV-2的复制和COVID-19的进展。 将通过关联COVID-19患者的外显子组来识别符合这一假设的遗传变异（目标1） 他们的纵向神经系统表现。因为PERK代表一个 已知这种基因是SARS冠状病毒感染所必需， 等位基因是AD/tau蛋白病的有效风险因素，我们将测量（目的2）SARS- AD/tau蛋白病中CoV-2刺突蛋白和3a蛋白的生物合成以及表达它们的神经元的存活 PERK激酶途径中的变体。变异，如亚纯型PERK等位基因将是一个可能的 对COVID-19敏感性差异很大的机制解释。未来的工作将验证，通过细胞 和分子方法，在Aim 1中确定的其他AD基因影响COVID-19。除了测试 AD/tau蛋白病等位基因与COVID-19和神经系统并发症风险改变的遗传联系， 研究将测试小分子药物，这些药物可以影响病毒的产生，也是治疗糖尿病的候选药物。 神经变性

Abstract: This competitive revision will extend the original grant “PERK determines polarized targeting of growth factors in neurons” (1R21AG063029), to explore how human genetic variants in Alzheimer’s disease–linked genes, including PERK, affect neuronal sensitivity to SARS-CoV-2 infection. A significant number of AD/tauopathy genes either contribute to the secretory function of cells (when wild type), or disrupt it and cause ER stress and translational silencing (when mutated or damaged). On the other hand, coronaviruses subvert the host cell ER and translational machinery to produce their own proteins. Thus, AD alleles that impact these pathways are hypothesized here to also impact replication of the novel SARS-CoV-2 and the progression of COVID-19. Genetic variants that fit this hypothesis will be identified (Aim 1) by relating the exomes of COVID-19 patients at Geisinger’s Health Center to their longitudinal neurological presentation. Because PERK represents one such gene that is already known to both be required for SARS coronavirus infection and to harbor hypomorphic alleles that are a validated risk factor for AD/tauopathy, we will measure (Aim 2) the dependence of SARS- CoV-2 Spike and 3a proteins biosynthesis, and the survival of neurons expressing them, on AD/tauopathy variants in the PERK kinase pathway. Variants such as hypomorphic PERK alleles will be one likely mechanistic explanation for the wide variation in sensitivity to COVID-19. Future work will validate, by cellular and molecular approaches, other AD genes identified in Aim 1 as affecting COVID-19. In addition to testing the genetic connection of AD/tauopathy alleles to altered risk for COVID-19 and neurological complications, our studies will test small molecule drugs that can affect virus production and are also candidates for treatment of neurodegeneration.