Defining the Mechanism of Meiotic Initiation Through Autophagy Pathway

项目总结 自噬是细胞降解和回收蛋白质和细胞器的过程。自噬是有缺陷的 促进自噬可以减轻AD模型中与AD相关的组织病理学。在AD中，原因和 扰动自噬的后果还没有完全被理解，我们现在提出的工作将是理想的 解决这一知识鸿沟。具体地说，维甲酸基因8(STRA8)最初被描述为 一种生殖细胞特有的蛋白质，需要启动减数分裂。我们是第一个将STRA8功能报告为 自噬抑制因子。因此，Stra8基因敲除会激活自噬。基于此，我们的R01-HD103888 研究STRA8在生殖细胞发育和减数分裂中对自噬的抑制作用。在我们的研究过程中， 我们发现STRA8出人意料地在小鼠脑细胞中表达。在功能上，我们的数据显示Stra8-KO小鼠 在他们的大脑中表现出更多的自噬，这表明STRA8作为自噬的抑制者的作用是 在生殖系和脑细胞中都是保守的。重要的是，在老化的小鼠大脑中，我们发现STRA8展示了 纺锤形堆积。此外，我们的数据显示，在尸检中，STRA8的mRNA表达水平升高 从年龄匹配的AD和非AD患者的脑中提取样本，并检测到STRA8蛋白的积累 在人类阿尔茨海默病大脑中。这些观察将STRA8与AD联系在一起，要么作为一种蛋白质，其生物学特性随着一部分发生变化 阿尔茨海默病中的代偿反应或作为一种蛋白质，有助于蛋白质内稳态的恶化 广告。随着STRA8抑制自噬，STRA8水平在衰老和AD大脑中增加，而AD 大脑表现出有缺陷的自噬和蛋白质应激，这两种情况都可能扰乱神经元的完整性。这 家长R01-HD103888拨款的行政补充将延长我们对STRA8介导的研究 从生殖细胞发育抑制自噬，成为AD发病机制研究的新热点。我们的 假设STRA8的表达上调，通过抑制自噬，可以改变AD的组织学 转基因AD小鼠模型中的变化、神经功能障碍、神经退行性变和行为。在目标1中，我们 将研究Stra8基因缺失是否改善了5XFAD小鼠AD的生化和行为特征。 在目标2中，我们将确定异位STRA8过表达是否会导致蛋白质动态平衡失调和神经元 在正常小鼠中丢失，并加剧5XFAD小鼠的AD发病。所获得的知识将为 STRA8在AD发病机制中的潜在新作用以及STRA8是否可以作为一种新的AD 治疗靶点。此外，文献声称AD神经元重新进入细胞周期。STRA8的S在片中的角色 发展可能在AD的这一方面提供信息，并在异常细胞周期和 令人不安的自噬。

PROJECT SUMMARY Autophagy is the process by which cells degrade and recycle proteins and organelles. Autophagy is defective in AD, and promoting autophagy mitigates AD-associated histopathology in AD models. In AD, the causes and consequences of perturbed autophagy are not entirely understood and the work we now propose will ideally address this knowledge gap. Specifically, stimulated by retinoic acid gene 8 (STRA8) was initially described as a germ cell-specific protein required for meiotic initiation. We are the first to report STRA8 functions as a suppressor of autophagy. As such, Stra8 knockout activates autophagy. Based on this, our R01-HD103888 studies STRA8-mediated suppression of autophagy in germ cell development and meiosis. During our studies, we found STRA8 is unexpectedly expressed in mouse brain cells. Functionally, our data show Stra8-KO mice exhibit increased autophagy in their brains, indicating that the role of STRA8 as a suppressor of autophagy is conserved in both germline and brain cells. Importantly, in aged mouse brains, we found that STRA8 exhibits spindle-shaped accumulation. Moreover, our data show that STRA8 mRNA expression is elevated in autopsied samples from age-matched human AD versus non-AD brains and that STRA8 protein accumulation is detected in human AD brains. These observations link STRA8 to AD, either as a protein whose biology changes as part of a compensatory response in AD or as a protein that contributes to the deterioration of protein homeostasis in AD. As STRA8 acts to suppress autophagy, STRA8 levels increase during aging and in AD brains, and AD brains exhibit defective autophagy and protein stress, either scenario likely perturbs neuronal integrity. This Administrative Supplement to the parent R01-HD103888 grant will extend our studies of STRA8-mediated autophagy suppression from germ cell development and develop a new focus in AD pathogenesis. Our hypothesis is that upregulated STRA8 expression, through its repression of autophagy, can modify AD histology changes, neurodysfunction, neurodegeneration, and behavior in a transgenic AD mouse model. In Aim 1, we will investigate whether Stra8 deletion improves the biochemical and behavioral hallmarks of AD in 5XFAD mice. In Aim 2, we will determine whether ectopic STRA8 overexpression induces protein dyshomeostasis and neuron loss in normal mice and exacerbates AD pathogenesis in 5XFAD mice. Knowledge obtained will inform a potential novel role for STRA8 in AD pathogenesis and address whether STRA8 could serve as a novel AD therapeutic target. Moreover, the literature claims AD neurons re-enter the cell cycle. STRA8’s role in development may inform this aspect of AD and serve as a molecular bridge between aberrant cell cycling and perturbed autophagy.