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: 8415348
• 负责人: Patrick M McLendon
• 金额: $ 0.9万
• 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 2013-03-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415348
• 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.

描述(申请人提供)：CryAB(CryABR120G)Arg120Gly突变可导致结蛋白相关的心肌病(DRM)，其特征是在转基因(TG)小鼠模型中心肌细胞肌浆中聚集的结蛋白和CryAB，导致心肌病和过早死亡。本实验室已鉴定出由CryABR120G突变形成的细胞内包涵体为侵袭体，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转基因小鼠含有淀粉样蛋白，该蛋白与一种针对细胞毒性淀粉样寡聚体(PAO)构象的抗体呈阳性染色，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质的正常机制中的功能缺陷引起的。这项拟议研究的目标是验证这样一种假设，即修复蛋白质降解途径的功能缺陷可以保护基于CryABR120G的心肌病，从而减少聚集形成并改善心功能。我们提出了两个特定的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中异常的蛋白质聚集：1)PAO的去除/降解由neprilysin(一种在类似疾病中降解可溶低聚物的蛋白质)将在CryABR120G的发病机制中产生积极的影响；2)通过减少蛋白质流向受损的降解隔室(通过降低Cochaperone/E3泛素连接酶芯片的水平来实现)，我们可以通过减少错误折叠蛋白质的流入来维持甚至恢复这些隔间的降解能力，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制在我们的模型中是否具有保护性。了解功能障碍降解在蛋白质构象疾病中所起的作用可以导致有针对性的治疗，以防止或推迟有毒蛋白质聚集体的发生，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。