Modification of genetic expression by intoronic microsatellite in risk genes of Alzheimer's disease

内含微卫星对阿尔茨海默病危险基因基因表达的修饰

• 批准号: 14570921
• 负责人: KAMINO Kouzin
• 金额: $ 2.24万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570921/
• 关键词: Apolipoprotein A-II; Apolipoprotein C-II; Alzheimer desease; microsatellite; spricing; Z-DNA; シスタチオニンβシンターゼ; アルブミン; アポリポ蛋白E

Serum lipid profile, especially apolipoprotein levels, in patients with late-onset Alzheimer's disease (LOAD) is altered compared to non-demented healty subjects, and the notable changes are decreased apolipoprotein A-II and A-I levels. We focused on microsatellite of Apolipoprotein (APO) genes, and examined the relation between their microsatellites in APO genes and the development of LOAD. First of all, we found that the total doses of microsattellite repeat in APOA-II gene is inversely correlated with age at onset of LOAD among APOE-e4 carriers (p<O.OO1). This microsatellite locates spricing acceptor site of exon 3 of APOA-II gene, and the longer the microsatellite length was related to the increased amount of mRNA lacking exon 3 and decreased amount of intact mRNA. However, mRNA lacking exon 3 did not produce protein product of apolipoprotein A-II, and it was thought that the microsatellite length was correlated with the amount of apolipoprotein A-II. On the other hand, ** also exa … More mined the microsatellite of APOC-II gene, which harbors microsatellite after the first transcribed region, and it locates nearby Apolipoprotein E gene, a risk gene of LOAD. We found that the total doses of microsatellite repeat is also correlated with age at onset of LOAD (p<O.O0O1). This effect was also significant in APOE-e4 carriers. Plasma apolipoprotein C-II level was inversely correlated with the total doses of the microsatellite repeat (p<0.05). Therefore, we concluded that these microsatellite located in intronic sequences acts to modify the amount of expressed protein product. Since in aging, plasma apolipoprotein A-II decreases and plasma apolipoprotein C-II level increases, which could be enfluenced by aging factors. It has been shown that microsatellites tend to form Z-DNA structure. Therefore, microsatellite structure is targeted by aging factors, and likely participates as genetic factor modifed by aging in the development of LOAD. Our results suggest that some factors targeting microsatellite structure could be related with aging. Less

晚发性阿尔茨海默病（LOAD）患者的血脂谱，尤其是载脂蛋白水平与正常人相比发生了改变，其中最显著的改变是载脂蛋白A-II和A-I水平降低。本研究以载脂蛋白（Apolipoprotein，APO）基因的微卫星为研究对象，探讨了APO基因微卫星与LOAD发生的关系。首先，我们发现在APOE-e4携带者中，APOA-II基因微卫星重复序列的总剂量与LOAD发病时的年龄呈负相关（p<0.001）。该微卫星定位于APOA-Ⅱ基因外显子3的转录受体位点，微卫星长度越长，缺失外显子3的mRNA含量越高，完整mRNA含量越低。而缺失外显子3的mRNA不产生载脂蛋白A-II的蛋白产物，认为微卫星长度与载脂蛋白A-II的量相关。另一方面，** 也是exa ...更多信息 对载脂蛋白C-Ⅱ基因的微卫星进行了挖掘，发现该基因位于载脂蛋白E基因附近，是LOAD的危险基因。我们发现微卫星重复序列的总剂量也与LOAD发病时的年龄相关（p<0.0001）。这种效应在APOE-e4携带者中也很显著。血浆载脂蛋白C-II水平与微卫星重复序列总剂量呈负相关（p<0.05）。因此，我们的结论是，这些位于内含子序列的微卫星的行为，以改变表达的蛋白质产物的量。随着年龄的增长，血浆载脂蛋白A-II水平降低，载脂蛋白C-II水平升高，这可能与衰老因素有关。研究表明，微卫星倾向于形成Z-DNA结构。因此，微卫星结构是衰老因素的靶点，可能作为衰老修饰的遗传因素参与LOAD的发生。我们的研究结果表明，一些针对微卫星结构的因素可能与衰老有关。少

项目成果

Ohsawa I, Nishimaki K, Yasuda C, Kamino K, et al.: "Deficiency in a mitochondrial aldehyde dehydrogenase increases vulnerability to oxidative stress in PC12 cells."J Neurochem. 84. 1110-1117 (2003)

Ohsawa I、Nishimaki K、Yasuda C、Kamino K 等人：“线粒体醛脱氢酶的缺乏会增加 PC12 细胞对氧化应激的脆弱性。”J Neurochem。

Hattori H, Kamino K, et al.: "The tau protein of oral epithelium increases in Alzheimer's disease"Journal of Gerontology : Medical Sciences. 57A・1. M64-M70 (2002)

Hattori H、Kamino K等人：“阿尔茨海默病中口腔上皮的tau蛋白增加”《老年学杂志：医学科学》57A·1（2002年）。

紙野晃人, 武田雅俊: "痴呆の遺伝因子"老年精神医学雑誌. 14・11. 1331-1337 (2003)

Akito Kamino、Masatoshi Takeda：“痴呆症的遗传因素”《老年精神病学杂志》14・11（2003）。

Hoshino T, Kamino K, et al.: "Dose of Apolipoprotein E-ε4 allele inversely correlates to plasma high-density lipoprotein cholesterol level in patients with Alzheimer's disease"Neurobiology of Aging. 23・1. 41-45 (2002)

Hoshino T、Kamino K 等人：“载脂蛋白 E-ε4 等位基因的剂量与阿尔茨海默氏病患者的血浆高密度脂蛋白胆固醇水平呈负相关”《衰老神经生物学》23・1（2002 年）。

紙野晃人: "遺伝子医学別冊/遺伝子医学の基礎知識:アルツハイマー病の分子病態解析"メディカル デゥ. 5 (2003)

上野明人：《遗传医学专刊/遗传医学基础知识：阿尔茨海默病的分子病理分析》医学杜5(2003)。