Ubiquilin and Alzheimer's Disease

泛素和阿尔茨海默病

基本信息

批准号：
7930558
负责人：
Jose Manuel Barral
金额：
$ 16.09万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7930558
关键词：
Address Affect Aging Alzheimer&apos s Disease Amyloid beta-Protein Precursor Binding Biochemical Biological Assay C-terminal Cell Line Cell surface Cells Client Cytoplasmic Tail Dementia Disease Disease Progression Elderly Endoplasmic Reticulum Event Gatekeeping Genes Genetic Golgi Apparatus Hybrids Impaired cognition In Vitro Individual Inherited Late Onset Alzheimer Disease Length Life Link Maps Methods Molecular Molecular Chaperones Mutation Neurodegenerative Disorders Neurons PC12 Cells Pathogenesis Pathway interactions Peptide Fragments Peptides Physiological Production Protein Binding Protein C Protein Fragment Proteins Proteolytic Processing Quality Control Regulation Reporting Series Single Nucleotide Polymorphism Site-Directed Mutagenesis Sorting - Cell Movement System Toxic effect UBA Domain Ubiquitin Yeasts aging population amyloid precursor protein processing base cellular imaging early onset in vitro testing insight multicatalytic endopeptidase complex neuron loss new therapeutic target novel prevent protein aggregation protein folding protein protein interaction protein transport public health relevance secretase trafficking ubiquilin

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with aging. Insight into the molecular basis of AD progression has been facilitated by the study of rare familial mutations which result in altered proteolytic processing of amyloid precursor protein (APP). One of the proteolytic products of APP, A2 peptide, is prone to aggregation and likely contributes to neuronal loss and cognitive dysfunction in AD. Unlike familial cases of AD, the underlying causes of late-onset AD are poorly understood. Genetic studies indicate that the UBQLN1 gene may be linked to late-onset AD. The protein product of the UBQLN1 gene, ubiquilin-1, is a modular protein which contains ubiquitin-like and ubiquitin-associated domains. Ubiquilin-1 also contains Sti1 domains implicated in protein-protein interactions and co-chaperone activity. These domains are present in several co-chaperone proteins, some of which have intrinsic molecular chaperone activity. A chaperone function for ubiquilin has not been demonstrated. We have found that ubiquilin has intrinsic molecular chaperone activity and binds to the cytosolic domain of APP. This binding directly modulates both the maturation and degradation of APP. The central hypothesis of this proposal is that ubiquilin is a key quality control molecule for APP folding and maturation: ubiquilin binds to and exerts chaperone activity on folding-competent APP species along the secretory pathway, whereas it targets misfolded APP to the proteasome system for degradation. This hypothesis will be addressed in three Specific Aims. In the first Aim, we will determine whether ubiquilin functions as a molecular chaperone for APP or APP fragments. In the second Aim, we will determine whether ubiquilin targets APP and/or APP proteolytic fragments for proteasomal degradation. Finally, in the third Aim we will determine whether ubiquilin modulates APP maturation and subsequent toxicity. Biochemical assays and live cell imaging will be used to determine how ubiquilin modulates APP maturation and degradation in cell lines and primary cortical neurons. We propose a novel function for ubiquilin as a molecular chaperone and hypothesize this function is critical for regulating the maturation, degradation and toxicity of APP. These studies may provide fundamental insights into the mechanistic basis of ubiquilin function in late-onset Alzheimer's disease. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most prevalent cause of dementia associated with aging. The molecular basis of AD progression in the aging population is poorly understood. This proposal will address the physiologic mechanisms by which the UBQLN1 gene product modulates amyloid precursor protein aggregation and toxicity, thus potentially revealing new therapeutic targets for this common disease.

描述（由申请人提供）：阿尔茨海默病（AD）是与衰老相关的最常见的神经退行性疾病。对罕见家族突变的研究促进了对 AD 进展的分子基础的深入了解，这些突变导致淀粉样前体蛋白 (APP) 的蛋白水解过程发生改变。 APP 的蛋白水解产物之一 A2 肽易于聚集，可能导致 AD 中的神经元丢失和认知功能障碍。与 AD 家族病例不同，人们对迟发性 AD 的根本原因知之甚少。遗传学研究表明 UBQLN1 基因可能与迟发性 AD 相关。 UBQLN1 基因的蛋白质产物 ubiquilin-1 是一种模块化蛋白质，包含泛素样域和泛素相关域。 Ubiquilin-1 还包含与蛋白质-蛋白质相互作用和共伴侣活性有关的 Sti1 结构域。这些结构域存在于几种共伴侣蛋白中，其中一些具有内在的分子伴侣活性。泛素的伴侣功能尚未得到证实。我们发现泛素具有内在的分子伴侣活性并与 APP 的胞质结构域结合。这种结合直接调节 APP 的成熟和降解。该提案的中心假设是泛素是 APP 折叠和成熟的关键质量控制分子：泛素沿着分泌途径与有折叠能力的 APP 物种结合并发挥伴侣活性，而它将错误折叠的 APP 靶向蛋白酶体系统进行降解。这一假设将在三个具体目标中得到解决。在第一个目标中，我们将确定泛素是否充当 APP 或 APP 片段的分子伴侣。在第二个目标中，我们将确定泛素是否以 APP 和/或 APP 蛋白水解片段为目标进行蛋白酶体降解。最后，在第三个目标中，我们将确定泛素是否调节 APP 成熟和随后的毒性。生化测定和活细胞成像将用于确定泛素如何调节细胞系和初级皮质神经元中 APP 的成熟和降解。我们提出了泛素作为分子伴侣的新功能，并假设该功能对于调节 APP 的成熟、降解和毒性至关重要。这些研究可能为晚发性阿尔茨海默病中泛素功能的机制基础提供基本见解。公共卫生相关性：阿尔茨海默氏病 (AD) 是与衰老相关的痴呆症的最常见原因。老年人群 AD 进展的分子基础尚不清楚。该提案将解决 UBQLN1 基因产物调节淀粉样前体蛋白聚集和毒性的生理机制，从而有可能揭示这种常见疾病的新治疗靶点。