Impaired Protein Degradation Pathways in Cardiac Proteinopathy

心脏蛋白病中蛋白质降解途径受损

• 批准号: 8255170
• 负责人: Patrick M McLendon
• 金额: $ 5.22万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-11 至 2014-01-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8255170
• 关键词: Affect; Alzheimer' s Disease; Amyloid; Animals; Antibodies; Brain; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Death; Cell physiology; Cessation of life; Crystallins; Data; Defect; Degenerative Disorder; Degradation Pathway; Desmin; Disease; Ensure; Environment; Excision; Exercise; Functional disorder; Genes; Genetic; Goals; Heart; Heart Diseases; Heart failure; Heat shock proteins; Homeostasis; Human; Huntington Disease; Impairment; Inclusion Bodies; Lead; Metalloproteases; Microfilaments; Modality; Modeling; Molecular; Molecular Chaperones; Molecular Conformation; Mus; Mutation; Neprilysin; Nerve Degeneration; Neurodegenerative Disorders; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Phenotype; Play; Production; Protein Conformation; Protein Family; Protein Precursors; Proteins; Quality Control; Research; Role; Route; Sarcomeres; Sarcoplasm; Staining method; Stains; Stress; Testing; Therapeutic; Tissues; Toxic effect; Transgenic Mice; Work; base; cytotoxic; disease phenotype; functional restoration; heart function; improved; member; mouse model; overexpression; premature; prevent; protein aggregate; protein aggregation; protein degradation; protein misfolding; protein transport; restoration; stem; therapeutic target; trafficking; ubiquitin-protein ligase; wasting

DESCRIPTION (provided by applicant): Arg120Gly mutations in CryAB (CryABR120G) can cause desmin-related cardiomyopathy (DRM), which is characterized by accumulation of aggregated desmin and CryAB in the sarcoplasm of cardiomyocytes, leading to cardiomyopathy and premature death in transgenic (TG) mouse models. Our lab has identified the intracellular inclusion bodies formed by CryABR120G mutations as aggresomes, which have similar morphological features to the protein aggregates observed in many neurodegenerative diseases. Indeed, CryABR120G TG mice contain amyloid-like proteins that are positively stained with an antibody targeting the conformation of a cytotoxic pre-amyloid oligomer (PAO), suggesting that DRM is a cardiac protein conformation disease which may be prevalent in many forms of human heart failure. Data suggests that the aggregation phenotype is caused, in part, by functional defects in the normal mechanisms of degrading misfolded proteins. The goal of the proposed research is to test the hypothesis that restoring functional deficits in protein degradation pathways can be protective in CryABR120G-based cardiomyopathy, leading to a reduction in aggregate formation and improved heart function. We have proposed two specific aims to test how modulating components of protein degradation routes can affect aberrant protein aggregation in CryABR120G-based DRM: 1) PAO removal/degradation by neprilysin, a protein shown to degrade soluble oligomers in similar diseases, will impact favorably on CryABR120G pathogenesis and 2) By decreasing protein traffic towards impaired degradation compartments (achieved by reducing the level of the cochaperone/E3 ubiquitin ligase CHIP), we can maintain or even restore the degradation capacity of these compartments by reducing the influx of misfolded protein, which will reduce protein accumulation and toxicity. The proposed studies will determine if protein aggregation in CryABR120G is caused by deficits in protein degradation machinery in the heart and, more importantly, determine if genetic modulation of these pathways can be protective in our model. Understanding the role played by malfunctioning degradation in protein conformation diseases could lead to targeted therapeutics to prevent or delay the onset of toxic protein aggregates, and may be widely applicable to a host of similar disease phenotypes in the heart and other tissues. PUBLIC HEALTH RELEVANCE: Many diseases of the heart and brain are due to protein misfolding, which causes degeneration and cell death. I will study two genes, neprilysin and CHIP, known to remove toxic misfolded proteins, which may delay or prevent heart disease. Improving protein removal may offer a therapeutic avenue to treat degenerative diseases.

描述（由申请人提供）：CryAB中的Arg120Gly突变（CryABR120G）可引起desmin相关性心肌病（DRM），其特征是聚集的desmin和CryAB在心肌细胞的肌浆中积累，导致转基因（TG）小鼠模型的心肌病和过早死亡。我们的实验室已经鉴定出由CryABR120G突变形成的细胞内包涵体为聚集体，其形态特征与许多神经退行性疾病中观察到的蛋白质聚集体相似。事实上，CryABR120G TG小鼠含有淀粉样蛋白，这种蛋白被靶向细胞毒性前淀粉样寡聚物（PAO）构象的抗体阳性染色，这表明DRM是一种心脏蛋白构象疾病，可能在许多形式的人类心力衰竭中普遍存在。数据表明，聚集表型部分是由降解错误折叠蛋白的正常机制中的功能缺陷引起的。该研究的目的是验证一种假设，即恢复蛋白质降解途径的功能缺陷可以保护基于cryabr120g的心肌病，导致聚集体形成减少和心功能改善。我们提出了两个具体目标来测试蛋白质降解途径的调节成分如何影响基于cryabr120g的DRM中的异常蛋白质聚集：1)通过neprilysin（一种可降解类似疾病中可溶性低聚物的蛋白质）去除/降解PAO将有利于CryABR120G的发病机制；2)通过减少受损降解区室的蛋白质运输（通过降低cochaperone/E3泛素连接酶CHIP的水平实现），我们可以通过减少错误折叠蛋白的流入来维持甚至恢复这些区室的降解能力，从而减少蛋白质的积累和毒性。拟议的研究将确定CryABR120G中的蛋白质聚集是否由心脏中蛋白质降解机制的缺陷引起，更重要的是，确定这些途径的遗传调节是否可以在我们的模型中起到保护作用。了解蛋白质构象疾病中降解故障所起的作用，可能会导致有针对性的治疗方法，以防止或延迟有毒蛋白质聚集的发生，并可能广泛适用于心脏和其他组织中许多类似的疾病表型。