Roles of Reticulon proteins in neurodegenerative disease

Reticulon 蛋白在神经退行性疾病中的作用

• 批准号: 7007640
• 负责人: RIQIANG YAN
• 金额: $ 30.63万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7007640
• 关键词: Alzheimer' s disease; SDS polyacrylamide gel electrophoresis; aging; amyloid proteins; endopeptidases; enzyme activity; genetically modified animals; immunocytochemistry; laboratory mouse; neural degeneration; protein structure function; western blottings

Alzheimer's disease is the most common age-related neurodegenerative disorder. It has been widely accepted that abnormal production or accumulation of amyloidogenic peptides (Abeta), derived from sequential processing of amyloid precursor protein (APP) by beta-secretase and gamma-secretase, is tightly linked to AD pathogenesis. Our main research objectives will be focused on the regulated APP processing and production of (Abeta) in cells. A type I transmembrane aspartyl protease have been recently identified as beta-secretase, or called BACE1. We believe that all physiological functions are well balanced by various negative and positive modifiers. It is conceivable that BACE1 activity in cells is also modulated by natural factors and a shift of the modulating balance will clearly affect Abeta production. We hypothesize that abnormal fluctuations of BACE1 modifiers in human brains contribute to the amyloid depositions and the subsequent AD pathogenesis. Recently, we found that reticulon 3 (RTN3) clearly modulates BACE1 activity. RTN3 is one of the members of RTN family that comprises four members and all the members share highly conserved C-terminal Reticulon Homology Domain (RHD). Our specific objectives in this proposal are to delineate the molecular mechanism in which RTN3, and probably its family members, negatively modulate BACE1 activity and to explore potential applications of reticulon proteins in Alzheimer's therapeutics. Vigorous biochemical, molecular cell biology approaches combined with genetic methods will be used to address the following Specific Aims. Aim 1 -To investigate interactions of BACE1 with RTN family members. Aim 2 - To explore the mechanism by which BACE1 activity is modified by RTN3. Aim 3 To validate RTN3 as a negative BACE1 modifier in vivo. We believe that results from this study will provide valuable insights into the molecular mechanisms of RTN3 and its family members in negatively modulating BACE1 activity.

阿尔茨海默病是最常见的与年龄相关的神经退行性疾病。 人们普遍认为，β-分泌酶和γ-分泌酶对淀粉样前体蛋白(APP)的连续加工产生的淀粉样肽(Abeta)的异常产生或积累与AD发病机制密切相关。我们的主要研究目标将集中在细胞中受监管的 APP 加工和 (Abeta) 生产。 I 型跨膜天冬氨酰蛋白酶最近被鉴定为β-分泌酶，或称为BACE1。我们相信，所有的生理功能都可以通过各种消极和积极的调节因素得到很好的平衡。可以想象，细胞中的 BACE1 活性也受到自然因素的调节，调节平衡的改变将明显影响 Abeta 的产生。我们假设人脑中 BACE1 修饰因子的异常波动导致淀粉样蛋白沉积和随后的 AD 发病机制。最近，我们发现 reticulon 3 (RTN3) 明显调节 BACE1 活性。 RTN3是RTN家族的成员之一，该家族由四个成员组成，所有成员都共享高度保守的C端网状同源结构域(RHD)。我们在本提案中的具体目标是描绘 RTN3 及其家族成员负向调节 BACE1 活性的分子机制，并探索网状蛋白在阿尔茨海默病治疗中的潜在应用。将采用强有力的生化、分子细胞生物学方法与遗传学方法相结合来实现以下具体目标。目标 1 - 研究 BACE1 与 RTN 家族成员的相互作用。目标 2 - 探索 RTN3 修饰 BACE1 活性的机制。目标 3 验证 RTN3 在体内作为负 BACE1 修饰剂。我们相信，这项研究的结果将为了解 RTN3 及其家族成员负向调节 BACE1 活性的分子机制提供有价值的见解。