Contribution of HUWE1 to sex differences in aging and Alzheimer's disease

项目摘要 直到最近，染色体性别对衰老和阿尔茨海默病（AD）中性别相关差异的贡献在很大程度上被忽视了。由于女性拥有两条X染色体，许多部分逃避X失活的基因在女性中可以以更高的水平表达。逃避X染色体失活发生与老化和失活逃避的程度不同的基因和细胞类型。含HECT、乌巴和WWE结构域的蛋白1（HUWE1）是E3泛素连接酶，其泛素化超过40种底物。HUWE1泛素化并诱导DNA损伤反应蛋白、转录因子和其他蛋白质的降解。Huwe1基因位于X染色体上，与X染色体连锁的智力残疾相关。由于重复事件导致HUWE1剂量增加导致儿童智力残疾，女性正常或症状低于男性，可能是由于X染色体失活。Huwe 1的突变也会导致智力残疾，女性也会像男性一样受到严重影响。HUWE1是否在衰老和AD中起作用尚未研究。在我们的数据中，我们发现HUWE1在老年雌性小鼠大脑中的水平高于年轻大脑。因此，拟议研究的主要目的是调查Huwe1是否在雌性Tg2576和Tau p301 s小鼠（及其非Tg对照）以及患有和不患有AD的女性人类的脑中逃脱失活，并确定HUWE1在年轻和老年、雄性和雌性Tg2576和Tau p301 s小鼠（其非Tg对照）脑中的相互作用组。由于临床研究已经证明治疗剂在男性和女性患者中的疗效不同，因此性别特异性机制的鉴定具有显著的翻译相关性。

Project Summary Until recently, the contribution of chromosomal sex to sex-associated differences in aging and Alzheimer's disease (AD) has been largely ignored. As females possess two X chromosomes, many genes that partially escape X inactivation could be expressed at higher levels in females. Escape from X chromosome inactivation occurs with aging and the degree of inactivation escape varies between genes and cell types. The HECT, UBA and WWE domain containing protein 1 (HUWE1) is an E3 ubiquitin ligase that ubiquitinates over 40 substrates. HUWE1 ubiquitinates and induces the degradation of DNA damage response proteins, transcription factors, and other proteins. The Huwe1 gene is located on the X chromosome and associated with X chromosome-linked intellectual disability. Increased dosages of HUWE1 due to duplication events result in intellectual disability in children with females being normal or less symptomatic than males, likely due to X chromosome inactivation. Mutations in Huwe1 lead to intellectual disability as well, and females can also be severely affected as males. Whether HUWE1 plays a role in aging and AD is not studied. In our data, we discovered that HUWE1 levels are higher in aged female mouse brains compared to young brains. Thus, the primary objective of the proposed studies is to investigate whether Huwe1 escapes inactivation in the brain of female Tg2576 and Tau p301 s mice (and their non-Tg controls), and female humans with and without AD and to determine HUWE1's interactome in the brain of young and aged, male and female Tg2576 and Tau p301s mice (their non-Tg controls). Since clinical research has demonstrated variable efficacy of therapeutic agents in male and female patients, identification of sex-specific mechanisms has significant translational relevance.