Maruyama Takuma, Abe Yoichiro, Niikura Takako
Department of Information and Communication Sciences, Faculty of Science and Technology, Sophia University, Japan.
Department of Pharmacology, Keio University School of Medicine, Japan.
Heliyon. 2018 Apr 13;4(4):e00601. doi: 10.1016/j.heliyon.2018.e00601. eCollection 2018 Apr.
Amyloid β, a key molecule in the pathogenesis of Alzheimer's disease (AD), is produced from amyloid precursor protein (APP) by the cleavage of secretases. APP is SUMOylated near the cleavage site of β-secretase. SUMOylation of APP reduces amyloid β production, but its regulatory system is still unclear. SUMOylation, a modification at a lysine residue of a target protein, is mediated by activating, conjugating, and ligating enzymes and is reversed by a family of sentrin/SUMO-specific proteases (SENPs). Here, we found that both SENP1 and SENP2 induced de-SUMOylation of APP. Using quantitative PCR, we also found that expression of SENP1 but not SENP2 increased in an age-dependent manner only in female mice. The results of immunoblot analyses showed that the protein expression was consistent with the PCR results. Females, compared to males, have a higher incidence of AD in humans and show more aggressive amyloid pathology in AD mouse models. Our results provide a clue to understanding the role of SUMOylation in the sex difference in AD pathogenesis.
淀粉样β蛋白是阿尔茨海默病（AD）发病机制中的关键分子，它由淀粉样前体蛋白（APP）经分泌酶切割产生。APP在β-分泌酶切割位点附近发生小泛素样修饰蛋白（SUMO）化。APP的SUMO化会减少淀粉样β蛋白的产生，但其调控系统仍不清楚。SUMO化是一种在靶蛋白赖氨酸残基上的修饰，由激活酶、缀合酶和连接酶介导，并被小泛素样修饰特异性蛋白酶（SENP）家族逆转。在此，我们发现SENP1和SENP2均可诱导APP去SUMO化。通过定量PCR，我们还发现仅在雌性小鼠中，SENP1而非SENP2的表达呈年龄依赖性增加。免疫印迹分析结果表明，蛋白质表达与PCR结果一致。在人类中，女性患AD的发病率高于男性，并且在AD小鼠模型中表现出更严重的淀粉样病理变化。我们的研究结果为理解SUMO化在AD发病机制性别差异中的作用提供了线索。
