Translational regulation in Alzheimer's Disease

阿尔茨海默病的转化调控

• 批准号: 6576435
• 负责人: LESLIE A KRUSHEL
• 金额: $ 7.57万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6576435
• 关键词: Alzheimer's disease; aging; amyloid proteins; brain circulation; cell line; disease /disorder etiology; endopeptidases; genetic regulation; genetic regulatory element; genetic translation; human genetic material tag; hypoxia; laboratory rat; messenger RNA; neurons; newborn animals; nucleic acid sequence; nucleic acid structure; pathologic process; presenilin; terminal nick end labeling; tissue /cell culture; transfection

Chronic hypofusion in the central nervous system, is hypothesized to predispose or lead to Alzheimer's Disease (AD). Increased expression and aggregation of an insoluble peptide, derived through the cleavage of the amyloid precursor protein (APP) by beta and gamma secretases, is thought to initiate plaque formation leading to cell death and the disease state. Hypoxia decreases protein synthesis by inhibiting the cap-binding/scanning mechanism for translation initiation, the major form of translation initiation. However, some mRNAs can also initiate translation in a cap-independent manner from internal ribosomal entry sites (IRESes) in the 5' leader. IRES dependent translation is unaffected or promoted by hypoxia. The hypothesis is that the 5' leaders of mRNAs encoding for proteins that contribute to the processing of APP, as well as APP, contain IRESes. In response to hypoxia, an increase in IRES dependent translation is predicted. Consequently, chronic hypoxia is hypothesized to lead to AD through a constant enhancement of IRESdependent translation with the concomitant increase of amyloid peptides. Accordingly, the proposed study will utilize neural cell lines and primary neurons grown in vitro as an assay system to answer the following questions: 1. Does the 5' leader of the APP mRNA and of the mRNAs encoding for proteins involved in the processing of APP including beta-secretases 1 and 2, and presenilins 1 and 2, contain IRESes? 2. Does hypoxia lead to an increase in IRES-dependent translation mediated by the AD-related 5' leaders? 3. What are the cis-elements in the 5' leaders of AD-related mRNAs that internally initiate translation in response to hypoxia? The proposed experiments will determine the mechanism of translation initiation of AD related mRNAs in response to hypoxia. The results will provide novel insights into the etiology of AD and present new avenues to explore for therapeutic intervention of individuals with AD or other vascular dementias.

据推测，中枢神经系统的慢性供血不足会诱发或导致阿尔茨海默病 (AD)。通过β和γ分泌酶裂解淀粉样前体蛋白(APP)而产生的不溶性肽的表达和聚集增加，被认为启动斑块形成，导致细胞死亡和疾病状态。缺氧通过抑制翻译起始的帽结合/扫描机制（翻译起始的主要形式）来减少蛋白质合成。然而，一些 mRNA 也可以以不依赖帽的方式从 5' 前导区的内部核糖体进入位点 (IRES) 启动翻译。 IRES 依赖性翻译不受缺氧影响或促进。假设 是编码有助于 APP 加工的蛋白质的 mRNA 的 5' 前导序列以及 APP 含有 IRES。为了应对缺氧，预计 IRES 依赖性翻译会增加。因此，假设慢性缺氧通过 IRES 依赖性翻译的不断增强以及淀粉样肽的伴随增加而导致 AD。因此，拟议的研究将利用体外生长的神经细胞系和原代神经元作为分析系统来回答以下问题： 1. APP mRNA 和编码蛋白质的 mRNA 的 5' 前导序列是否参与 APP 的加工包括 β 分泌酶 1 和 2，以及早老素 1 和 2，是否含有 IRES？ 2. 缺氧是否会导致 AD 相关 5' 前导序列介导的 IRES 依赖性翻译增加？ 3. AD 相关 mRNA 5' 前导序列中的顺式元件是什么，这些顺式元件在缺氧时内部启动翻译？ 拟议的实验将确定 AD 相关 mRNA 响应缺氧的翻译起始机制。这些结果将为 AD 病因学提供新的见解，并为探索 AD 或其他血管性痴呆患者的治疗干预提供新途径。