PERK determines polarized targeting of growth factors in neurons

PERK 确定神经元中生长因子的极化靶向

• 批准号: 9895969
• 负责人: TALI GIDALEVITZ
• 金额: $ 44.19万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895969
• 关键词: Affect; Afferent Neurons; Alleles; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Apoptosis; Apoptotic; Attenuated; Axon; Biochemical; Brain; Ca(2+)-Calmodulin Dependent Protein Kinase; Caenorhabditis elegans; Calcineurin; Calcium; Calcium Channel; Cells; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cognition; Data; Defect; Dendrites; Disease; Endoplasmic Reticulum; Estrogen receptor positive; Genetic; Growth Factor; Heart; Homeostasis; IGF1 gene; ITPR1 gene; Impairment; Ion Channel; Link; Mediating; Mediator of activation protein; Memory; Mitochondria; Modeling; Mus; Mutation; Nature; Nerve Degeneration; Neurons; PRKR gene; Pathologic; Pathway interactions; Pharmacology; Phenotype; Phosphorylation; Phosphotransferases; Process; Progressive Supranuclear Palsy; Protein Biosynthesis; Regulation; Reporting; Risk; Role; Ryanodine Receptor Calcium Release Channel; Short-Term Memory; Signal Transduction; Smell Perception; Stress; Symptoms; Synaptic Vesicles; Synaptic plasticity; Tauopathies; Testing; Transforming Growth Factor beta; Translations; Variant; Work; calmodulin-dependent protein kinase II; endoplasmic reticulum stress; genetic analysis; genetic risk factor; genetic testing; genetic variant; inhibitor/antagonist; insight; loss of function; neuronal growth; neuroprotection; novel; olfactory bulb; risk variant; sensor

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.

摘要 ER应激传感器PERK通常用于减弱蛋白质合成和激活凋亡途径。 因此，大多数将PERK与阿尔茨海默病和Tauophathies联系起来的工作都集中在操纵这个 活动然而，与神经变性风险增加相关的PERK基因变异， 最近被证明具有降低的激酶活性，这表明PERK途径也具有重要的 可能是神经保护的适应性功能。操纵这些保护功能同样重要 治疗神经退化我们发现了PERK的一个这样的功能，它是正确定位的基础。 生长因子的轴突和树突，这反过来是一个先决条件，为他们的地方分泌， 神经保护PERK参与生长因子的定位，因为它在小鼠皮质 神经元或蠕虫化学感觉神经元中的神经元的神经元神经元的神经元的神经元神经元神经 IGF和TGFβ的分泌。该提案探讨了PERK如何控制轴突/树突定位 并分泌这些神经保护性生长因子。 在目标1中，我们将确定PERK的激酶活性是否是神经元中生长因子定位所必需的， 其主要的磷酸化底物eIF 2 α是否介导了这种活性，以及PERK风险等位基因是否 与神经退行性变相关的改变生长因子的分布。在目标2中，我们将遵循遗传学 数据表明PERK对生长因子定位的调节依赖于钙离子的组分， 稳态机制，膜通道和胞质介质。在这两个目标中，我们将联合收割机 用生化分析对蠕虫和小鼠的感觉神经元进行遗传分析，因为 这些方法提供的互补见解。 该项目将确定一种新的细胞途径，该途径是生长因子极化分泌的基础， 神经元及其功能连接。了解PERK如何执行这种新颖的保护 神经元的功能将为在症状前AD和tau蛋白病中操纵这些通路提供选择 模型，并描绘敏化与保护机制。