载脂蛋白 E4 通过与 CLEAR 基序的直接、特异性结合来抑制自噬基因产物。
Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs.
机构信息
Donald W. Reynolds Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Donald W. Reynolds Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Geriatric Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
出版信息
Alzheimers Dement. 2018 Feb;14(2):230-242. doi: 10.1016/j.jalz.2017.07.754. Epub 2017 Sep 22.
INTRODUCTION
Alzheimer apolipoprotein E (APOE) ɛ4/ɛ4 carriers have earlier disease onset and more protein aggregates than patients with other APOE genotypes. Autophagy opposes aggregation, and important autophagy genes are coordinately regulated by transcription factor EB (TFEB) binding to "coordinated lysosomal expression and regulation" (CLEAR) DNA motifs.
METHODS
Autophagic gene expression was assessed in brains of controls and Alzheimer's disease (AD) patients parsed by APOE genotype and in a glioblastoma cell line expressing either apoE3 or apoE4. Computational modeling assessed interactions between apoE and mutated apoE with CLEAR or modified DNA.
RESULTS
Three TFEB-regulated mRNA transcripts-SQSTM, MAP1LC3B, and LAMP2-were lower in AD ɛ4/ɛ4 than in AD ɛ3/ɛ3 brains. Computational modeling predicted avid specific binding of apoE4 to CLEAR motifs. ApoE was found in cellular nuclei, and in vitro binding assays suggest competition between apoE4 and TFEB at CLEAR sites.
CONCLUSION
ApoE4-CLEAR interactions may account for suppressed autophagy in APOE ɛ4/ɛ4 carriers and, in this way, contribute to earlier AD onset.
简介
载脂蛋白 E（APOE）阿尔茨海默氏症 ɛ4/ɛ4 携带者的发病时间比其他 APOE 基因型患者更早，且体内蛋白聚集体更多。自噬可对抗聚集，而重要的自噬基因则由转录因子 EB（TFEB）与“协调溶酶体表达和调节”（CLEAR）DNA 基序结合协调调控。
方法
通过 APOE 基因型对对照组和阿尔茨海默病（AD）患者的脑组织进行分类，评估自噬基因的表达情况，并在表达 apoE3 或 apoE4 的神经胶质瘤细胞系中进行评估。计算模型评估了 apoE 与突变 apoE 与 CLEAR 或修饰 DNA 之间的相互作用。
结果
在 AD ɛ4/ɛ4 患者的脑中，三个 TFEB 调控的 mRNA 转录本-SQSTM、MAP1LC3B 和 LAMP2-均低于 AD ɛ3/ɛ3 患者。计算模型预测 apoE4 与 CLEAR 基序有强烈的特异性结合。apoE 存在于细胞核中，体外结合实验表明 apoE4 和 TFEB 在 CLEAR 位点存在竞争。
结论
apoE4-CLEAR 相互作用可能解释了 APOE ɛ4/ɛ4 携带者中自噬受到抑制的原因，并因此导致 AD 发病更早。
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