APP MRNA DYSREGULATION AND ALZHEIMERS DISEASE

APP mRNA 失调与阿尔茨海默病

• 批准号: 2712122
• 负责人: James S Malter
• 金额: $ 17.17万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-29 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2712122
• 关键词: Alzheimer's disease; amyloid proteins; clinical research; gene induction /repression; heterogeneous nuclear ribonucleoprotein; human genetic material tag; human subject; messenger RNA; nucleic acid metabolism; nucleic acid sequence; posttranscriptional RNA processing; protein biosynthesis

DESCRIPTION The accumulation of AB protein in the central nervous system remains a hallmark of Alzheimer's Disease (AD). AB is proteolytically cleaved from the amyloid precursor protein (APP) which itself is over-expressed in neurons, glia and possibly peripheral cells and tissues. Patients with Down's Syndrome carry an extra APP allele, overexpress APP mRNA by 1.5-2 fold, deposit extracellular AB and inevitably develop AD. Recently, a family with autosomal dominant, early onset AD (EOAD) was identified with increased APP gene transcription and 1.6 fold normal, steady state APP mRNA levels. While it remains controversial, APP gene mRNA is likely over-expressed by 1.2-2 fold in CNS neurons of a subset of late onset AD patients as compared to age matched controls. Therefore, APP mRNA levels and the cellular mechanisms which control them are likely important in AD pathogenesis. The applicant has recently shown that APP mRNA stability is controlled by the regulated interactions of a 29 base, 3' untranslated region destabilizing element and two mRNA binding proteins, nucleolin and hnRNP C protein. The 29 base element is found in all amyloidogenic APP mRNAs as well as the murine homologue and destabilizes APP mRNA in resting cells. After cell stimulation, nucleolin and hnRNP C are activated, bind APP mRNA, causing its stabilization and accumulation. The applicant has also shown that small differences in APP mRNA content due to variable stability cause significant increases in APP production. Therefore, it is proposed that modest increases in APP mRNA content comparable to that seen in DS, an EOAD kindred and some AD patients can have significant effects on APP production. The applicant proposes to test the hypothesis that "increased APP production in part depends on APP mRNA stability which in turn is controlled by interactions between the 29 base element and hnRNP C and nucleolin." This will be tested by the studies (i) to identify the spatial organization and nucleotide sequence of the 29 base element regulating the decay of APP mRNA, (ii) to characterize how hnRNP C and nucleolin are activated to bind to APP mRNA, and (iii) determine the effects of APP mRNA stability and steady state levels on AP synthesis. Taken together, these studies will investigate the underlying mechanisms of APP mRNA posttranscriptional gene regulation and its consequences on APP and AB production.

描述 AB 蛋白在中枢神经系统中的积累 仍然是阿尔茨海默病（AD）的一个标志。 AB 具有蛋白水解作用 从淀粉样前体蛋白 (APP) 上切下，其本身是 在神经元、神经胶质细胞以及可能的外周细胞和组织中过度表达。 唐氏综合症患者携带额外的 APP 等位基因，即过度表达 APP mRNA增加1.5-2倍，沉积在细胞外AB并不可避免地发展为AD。 最近，一个患有常染色体显性早发性AD（EOAD）的家族 确定 APP 基因转录增加，是正常的 1.6 倍，稳定 状态 APP mRNA 水平。 尽管仍有争议，但 APP 基因 mRNA 是 在晚发型子集的 CNS 神经元中可能过度表达 1.2-2 倍 AD 患者与年龄匹配的对照组相比。 因此，APP mRNA 水平 控制它们的细胞机制可能在 AD 中很重要 发病。 申请人最近表明 APP mRNA 稳定性 由 29 个碱基、3' 未翻译的受调控相互作用控制 区域不稳定元件和两个 mRNA 结合蛋白，核仁素和 hnRNP C 蛋白。 29个碱基元素存在于所有淀粉样变性APP中 mRNA 以及小鼠同源物并在静息状态下破坏 APP mRNA 的稳定性 细胞。 细胞刺激后，核仁素和hnRNP C被激活，结合 APP mRNA，导致其稳定和积累。 申请人有 还表明，由于变量的影响，APP mRNA 含量存在微小差异。 稳定性导致 APP 产量显着增加。 因此，它是 提出 APP mRNA 含量的适度增加与所观察到的相当 在 DS 中，EOAD 亲属和一些 AD 患者可能会对 APP制作。 申请人建议检验以下假设： “APP 产量的增加部分取决于 APP mRNA 的稳定性，这在 转向由29个碱基元件和hnRNP C之间的相互作用控制 和核仁素。”这将通过研究 (i) 进行测试，以确定 29个碱基元素的空间组织和核苷酸序列 调节 APP mRNA 的衰变，(ii) 表征 hnRNP C 和 核仁素被激活以与 APP mRNA 结合，并且 (iii) 确定效果 APP mRNA 稳定性和 AP 合成的稳态水平。 采取 这些研究将共同​​探讨 APP 的潜在机制 mRNA转录后基因调控及其对APP和AB的影响 生产。