Division of Brain Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Chungcheongbuk-do, Republic of Korea.
Neurobiol Aging. 2013 Mar;34(3):650-62. doi: 10.1016/j.neurobiolaging.2012.08.005. Epub 2012 Sep 11.
Accumulation of disease-related proteins is a characteristic event observed in the pathogenesis of neurodegenerative diseases. β-secretase (BACE)-1, which initiates generation of β-amyloid (Aβ), is increased in the Alzheimer's diseased brain. However, the mechanisms of BACE1 accumulation in Alzheimer's disease are largely unknown. In this report, we found that small ubiquitin-like modifier (SUMO)-1 interacts with the dileucine motif of BACE1 and regulates the level of BACE1 protein. This was proved by the coimmunoprecipitation, and gain or loss of function experiments. Altering 3 SUMO isoforms affects BACE1 protein levels, and consequently results in altered amyloid precursor protein processing and Aβ generation. BACE1 levels were increased in response to Aβ or apoptosis, but not in cells lacking SUMO1. Aβ increased SUMO1 protein levels in rat cortical neurons. Moreover, SUMO1 immunoreactivity was increased in the amyloid precursor protein transgenic mice. Furthermore, the C-terminus fragments of BACE1 containing dileucine motif reduced Aβ generation by SUMO1 overexpression. Our study indicates SUMO1 is not only a novel and potent regulator of BACE1 accumulation and Aβ generation but also a potential therapeutic target for Alzheimer's disease.
疾病相关蛋白的积累是神经退行性疾病发病机制中观察到的一个特征性事件。β-分泌酶（BACE）-1 启动β-淀粉样蛋白（Aβ）的产生，在阿尔茨海默病大脑中增加。然而，BACE1 在阿尔茨海默病中的积累机制在很大程度上尚不清楚。在本报告中，我们发现小泛素样修饰物（SUMO）-1 与 BACE1 的双亮氨酸基序相互作用，并调节 BACE1 蛋白的水平。这通过共免疫沉淀和功能获得或缺失实验得到了证明。改变 3 种 SUMO 同种型会影响 BACE1 蛋白水平，从而导致淀粉样前体蛋白加工和 Aβ 生成的改变。BACE1 水平在响应 Aβ或细胞凋亡时增加，但在缺乏 SUMO1 的细胞中没有增加。Aβ 在大鼠皮质神经元中增加 SUMO1 蛋白水平。此外，淀粉样前体蛋白转基因小鼠中的 SUMO1 免疫反应性增加。此外，含有双亮氨酸基序的 BACE1 C 末端片段通过 SUMO1 过表达减少了 Aβ 的生成。我们的研究表明，SUMO1 不仅是 BACE1 积累和 Aβ 生成的新型有效调节剂，也是阿尔茨海默病的潜在治疗靶点。
