Investigating nucleo-cytoplasmic partitioning in Alzheimer's disease and aging

项目总结/摘要 蛋白质的核质分配是一个新兴的细胞内过程， 老年痴呆症和衰老核转运蛋白通过转运介导适当的分配 蛋白质穿过核孔。核转运蛋白的药理学调节提供了一种新的 治疗阿尔茨海默病的方法。 最近对模式生物和哺乳动物细胞的研究发现， 神经变性疾病显示出功能失调的核质蛋白质分配。我们 据报道，保守的karyopherin XPO 1通过促进细胞核内 长寿相关转录因子的输出，从而防止 蛋白质抑制机制具体来说，我们发现，抑制XPO 1导致寿命延长， 延伸并导致跨门增强的蛋白质稳态，部分通过自噬- 溶酶体途径XPO 1的水平在长寿动物中降低，我们最近的数据显示， 表明XPO 1介导的寿命调节依赖于转录组的基本变化， 蛋白质组分配以及核仁重组，这导致核糖体改变， 生物起源因此，我们假设XPO 1协调调节细胞核-细胞质 蛋白质分配和核仁形成，从而调节隔室特异性蛋白质 功能，核糖体生物合成，活性mRNA翻译和因此寿命。 为了解决这一假设，我们建议对蛋白质进行全局表征， 以及它对蛋白质稳定和衰老的影响。我们将联合收割机- 边缘遗传学和生物化学方法在C.和哺乳动物细胞来表征 衰老过程中蛋白质的核质分配（目标1），并最终揭示 新的核仁功能调节剂对阿尔茨海默病具有潜在的益处（Aim 2）。 这些拟议的研究是重要的，因为它们解决了与衰老相关的一个重要问题。 核质分配和核仁功能在生物体发育中的作用和调控 衰老我们的方法是创新的，因为我们使用C。线虫和哺乳动物细胞 快速鉴定特定的蛋白质翻译和蛋白质的分配与衰老的作用， 发现调节核仁和核糖体动力学的药理学策略， 预防老年痴呆症

PROJECT SUMMARY/ABSTRACT Nucleo-cytoplasmic partitioning of proteins is an emerging intracellular process with crucial roles in Alzheimer’s disease and aging. Karyopherins mediate proper partitioning by transporting proteins across the nuclear pore. Pharmacological modulation of karyopherins provides a new approach for therapies against Alzheimer’s disease. Recent studies in model organisms and mammalian cells have uncovered that several neurodegenerative diseases display dysfunctional nucleo-cytoplasmic protein partitioning. We have reported that the conserved karyopherin XPO1 accelerates aging by promoting the nuclear export of longevity-associated transcription factors, thereby preventing the maintenance of proteostatic mechanisms. Specifically, we showed that inhibiting XPO1 leads to lifespan extensions and results in enhanced proteostasis across phyla, in part via the autophagy- lysosomal pathway. Levels of XPO1 are reduced in long-lived animals and our recent data suggest that XPO1-mediated lifespan modulation relies on fundamental changes in transcriptome and proteome partitioning as well as nucleoli re-organization, which results in altered ribosomal biogenesis. Thus, we hypothesize that XPO1 coordinately modulates the nucleo-cytoplasmic partitioning of proteins and nucleoli formation, thereby regulating compartment-specific protein functions, ribosomal biogenesis, active mRNA translation and consequently lifespan. To address this hypothesis, we propose to conduct a global characterization of protein partitioning and specification and its impact on proteostasis and aging. We will combine cutting- edge genetics and biochemical approaches in C. elegans and mammalian cells to characterize the nucleo-cytoplasmic partitioning of proteins during aging (Aim 1) and, ultimately, to uncover new modulators of nucleolar function with potential benefits against Alzheimer’s disease (Aim 2). These proposed studies are significant as they address an important question in aging related to the role and regulation of nucleo-cytoplasmic partitioning and nucleoli function during organism aging. Our approaches are innovative since we utilize C. elegans and mammalian cells in parallel to quickly identify specific protein translation and partitioning of proteins with roles in aging and to uncover pharmacological strategies to modulate nucleolar and ribosomal dynamics and preventing Alzheimer’s disease.