Cell Biology of Presenilin 1 and Associated Proteins

早老素 1 和相关蛋白的细胞生物学

• 批准号: 7919038
• 负责人: GOPAL THINAKARAN
• 金额: $ 15.36万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919038
• 关键词: Accounting; Address; Affect; Age-Years; Aging; Alzheimer' s Disease; American; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Binding; Biochemical; Brain; C-terminal; Catalytic Domain; Cellular biology; Cerebrum; Coat Protein Complex I; Complex; Cultured Cells; Cytoplasmic Tail; Dementia; Deposition; Development; Disease; Elderly; Endoplasmic Reticulum; Experimental Models; Extracellular Matrix; Family; Genes; Golgi Apparatus; Hand; Individual; Inherited; Investigation; Knockout Mice; Knowledge; Lead; Link; Matrix Metalloproteinases; Mediating; Membrane; Membrane Glycoproteins; Membrane Proteins; Modeling; Molecular; Molecular Weight; Morphology; Mus; Mutation; Nervous system structure; Neuroglia; Neurons; Organelles; Pathogenesis; Patients; Peptide Hydrolases; Population; Presenile Alzheimer Dementia; Process; Production; Protein C; Proteins; Proteolysis; Proteolytic Processing; Publishing; Regulation; Reporting; Role; Senile Plaques; Small Interfering RNA; Techniques; Therapeutic; Transgenic Mice; Transport Vesicles; United States; aged; aging brain; amyloid peptide; amyloid precursor protein processing; autosomal dominant trait; base; beta-site APP cleaving enzyme 1; domain mapping; early onset; enzyme activity; familial Alzheimer disease; insight; member; nicastrin protein; notch protein; novel; novel therapeutics; peptide A; polypeptide; presenilin-1; presenilin-2; protein complex; protein metabolism; protein transport; public health relevance; receptor; secretase; sequential proteolysis; trafficking

DESCRIPTION (provided by applicant): Cerebral deposition of beta-amyloid peptides (AB) is one of the pathological hallmarks of Alzheimer's disease. AB is generated by sequential proteolysis of amyloid precursor protein (APP) by BACE1 and g-secretase. g-secretase is a multimeric protein complex made of four main subunits, namely PS1 (or PS2), nicastrin, PEN2 and APH-1, and a few regulatory subunits including CD147 and p23 (also referred to asTMP21). PS1 is thought to function as the catalytic subunit of g-secretase complex. Post-translational maturation and stability of the four core subunits of g-secretase are mutually regulated, and each of them is indispensable for functional enzyme activity. On the other hand, diminution of CD147 or p23 expression increases AB production, suggesting that these proteins negatively regulate g-secretase processing of APP. The specific mechanisms by which p23 modulates g-secretase cleavage of APP remain undetermined. Studies outlined in this proposal address the function of p23 in trafficking and g-secretase processing of APP in cultured cells and in mouse brains Specifically, we propose to elucidate the functional interaction between p23 and g-secretase subunits so that we can better understand the mechanisms by which p23 negatively regulates AB production. We will define the structural domains essential for p23's influence on APP trafficking and AB production, and investigate p23 modulation of AB deposition using p23 transgenic mice and p23 conditional knockout mice. Finally, we will investigate the details on p23's role in secretory and endocytic trafficking of APP and examine the relationship between Golgi morphology and AB production. Our investigation uses a combination of biochemical, molecular and cell biology techniques to accomplish the following specific aims. Aim 1: To study the functional interaction between p23 and g-secretase. Aim 2: To investigate p23 regulation of AB production and deposition in mouse brain. Aim 3: To determine the mechanisms linking p23 function with APP trafficking and g-secretase processing. Our studies address issues that are central to molecular Alzheimer's disease pathogenesis. We seek to investigate a novel aspect of g-secretase modulation by p23 that impacts on AB production. Our studies have the potential to uncover significant insights on p23 regulation of APP trafficking and AB production, and may lead to the development of p23-based novel therapeutic strategies aimed reducing AB burden by selective inactivation of g-secretase function in APP processing. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the major cause of dementia in the elderly, afflicting more than 50% of the population over 80 years of age; presently 5.1 million Americans suffer from this devastating disorder. AD patients as well as aged individuals accumulate beta-amyloid peptides as deposits in brain, called senile plaques. Using cultured cells, transgenic mice, and conditional knockout mice as experimental models we investigate the function a protein called p23 in regulating beta-amyloid production and deposition. Our studies will be critical to develop novel rational AD therapeutics aimed at reducing beta-amyloid burden in the brain.

描述（由申请人提供）：β-淀粉样蛋白肽（AB）的脑沉积是阿尔茨海默氏病的病理标志之一。 AB是通过BACE1和G-分泌酶对淀粉样蛋白前体蛋白（APP）的顺序蛋白水解产生的。 G-分泌酶是由四个主要亚基制成的多聚体蛋白质复合物，即PS1（或PS2），Nicastrin，PEN2和APH-1，以及包括CD147和P23在内的一些调节亚基（也称为ASTMP21）。 PS1被认为是G-分泌酶复合物的催化亚基。 G-分泌酶四个核心亚基的翻译后成熟和稳定性是相互调节的，并且它们对于功能性酶活性都是必不可少的。另一方面，CD147或P23表达的降低会增加AB的产生，这表明这些蛋白质对APP的G-分泌酶处理负面调节。 P23调节APP的G分泌酶裂解的特定机制仍未确定。该提案中概述的研究介绍了p23在培养细胞和小鼠大脑中的运输和G-分泌酶处理中的功能，我们建议阐明p23和G-分泌酶亚基之间的功能相互作用，以便我们可以更好地理解p23的机制对AB的生产进行负调节。我们将定义P23对APP运输和AB产生的影响至关重要的结构域，并使用P23转基因小鼠和P23条件敲除小鼠研究AB沉积的P23调节。最后，我们将调查有关P23在APP的分泌和内吞运输中的作用的细节，并研究Golgi形态与AB生产之间的关系。我们的研究结合了生化，分子和细胞生物学技术来实现以下特定目标。目标1：研究p23和G-分泌酶之间的功能相互作用。目标2：研究P23小鼠大脑中AB产生和沉积的调节。目标3：确定将P23功能与APP运输和G-分泌酶处理联系起来的机制。我们的研究解决了分子阿尔茨海默氏病发病机理的核心问题。我们试图通过P23调查G-分泌酶调节的新颖方面，从而影响AB生产。我们的研究有可能发现对P23 APP运输和AB生产的调节的重大见解，并可能导致基于P23的新型治疗策略的发展，旨在通过选择性失活G-分泌酶在应用程序处理中减少AB负担。 公共卫生相关性：阿尔茨海默氏病（AD）是老年人痴呆症的主要原因，遭受了80岁以上人口的50％以上；目前，有510万美国人患有这种毁灭性疾病。 AD患者以及老年人会积累β-淀粉样蛋白肽作为大脑的沉积物，称为老年斑块。使用培养的细胞，转基因小鼠和有条件的基因敲除小鼠作为实验模型，我们研究了在调节β-淀粉样蛋白产生和沉积的功能中称为p23的蛋白质。我们的研究对于开发旨在减轻大脑中β-淀粉样蛋白负担的新型理性AD疗法至关重要。