Role of Brain Ferroxidases in AD and sCJD Pathogenesis

脑铁氧化酶在 AD 和 sCJD 发病机制中的作用

• 批准号: 8338829
• 负责人: Neena Singh
• 金额: $ 22.73万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338829
• 关键词: 3' Untranslated Regions; Acetylcysteine; Affect; Alzheimer' s Disease; Antioxidants; Binding Proteins; Biological Assay; Brain; Cell Line; Cell model; Cells; Ceruloplasmin; Creutzfeldt-Jakob Syndrome; Data; Disease; Disease Progression; Down-Regulation; Electrophoretic Mobility Shift Assay; Etiology; Functional disorder; Future; Generations; Hamsters; Homeostasis; Human; Huntington Disease; Hydroxyl Radical; Immunohistochemistry; India; Infection; Iron; Joints; Laboratories; Mediating; Metals; Modeling; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pathogenesis; Phenotype; Play; PrP; PrPSc Proteins; Prion Diseases; Prions; Process; Protein Isoforms; Protein Precursors; Proteins; RNA; Reactive Oxygen Species; Reading; Regulation; Reporting; Role; Sampling; Scrapie; Shipping; Ships; Testing; Tg2576; Wild Type Mouse; Work; Zinc; base; brain tissue; design; familial Alzheimer disease; insight; iron deficiency; iron metabolism; mRNA Decay; mouse model; mutant; neuroblastoma cell; neurotoxicity; oxidative damage; protein complex; public health relevance; response; therapeutic development; uptake

DESCRIPTION (provided by applicant): Several neurodegenerative conditions such as sporadic Creutzfeldt-Jakob disease (sCJD), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are associated with imbalance of iron homeostasis in diseased brains, raising the possibility that redox-iron induced oxidative damage plays a significant role in the neurotoxicity associated with these disorders. Recent evidence from the Singh laboratory indicates a significant reduction of ferroxidase activity in sCJD affected human and scrapie infected mouse brains. Combined with the fact that sCJD brains show a phenotype of 'apparent' iron deficiency despite the presence of normal or increased brain iron levels, these observations suggest dysregulation of the normal iron homeostatic machinery in diseased brains. A recent report demonstrates decreased ferroxidase activity leading to iron accumulation in AD brains, suggesting that this phenomenon is shared by neurodegenerative disorders of disparate etiology. In an independent set of studies, the Mukhopadhayay laboratory reported that ceruloplasmin (Cp), a major ferroxidase in the brain, is down regulated by reactive oxygen species (ROS). Since iron is highly redox-active and a major contributor of ROS if mismanaged, it is likely that once initiated by a specific disease process, iron imbalance is perpetuated by ROS through down regulation of major brain ferroxidases. Based on these observations, we hypothesize that ROS mediated misregulation of brain specific ferroxidases contributes to iron imbalance in AD and sCJD. The proposed studies will test this hypothesis in two specific aims. In aim 1, the role of ROS in regulating specific ferroxidases will be investigated in cell models o AD and prion disease. Once the ferroxidases have been identified, their regulation will be compared with Cp which is known to be regulated by an mRNA decay mechanism in response to ROS. Subsequently, the minimal region of 3' UTR and binding proteins responsible for regulating ROS-mediated Cp activity will be identified. In aim 2, the ferroxidases identified in ai 1 will be evaluated for their expression and activity in mouse models of AD and scrapie infection during disease progression. The results will be compared with human brain tissue from AD and sCJD cases using ferroxidase assay and immunohistochemistry as the read-out. Successful completion of these studies will clarify the role of major brain ferroxidases in iron dyshomeostasis associated with AD and sCJD brains, and provide the ground-work for future studies on the mechanism of brain iron dyshomeostasis in PD, HD, and other neurodegenerative conditions associated with brain iron imbalance.

描述（由申请人提供）：一些神经退行性疾病，如散发性克雅氏病（sCJD）、阿尔茨海默病（AD）、帕金森病（PD）和亨廷顿病（HD）与患病大脑中铁稳态失衡有关，这提高了氧化还原铁诱导的氧化损伤在与这些疾病相关的神经毒性中起重要作用的可能性。最近来自Singh实验室的证据表明，sCJD感染的人和瘙痒病感染的小鼠大脑中氧化铁酶活性显著降低。再加上sCJD的大脑尽管存在正常或增加的脑铁水平，但仍表现出“明显”缺铁的表型，这些观察结果表明，患病大脑中正常的铁稳态机制失调。最近的一份报告表明，氧化铁酶活性降低导致阿尔茨海默病大脑中的铁积累，这表明这种现象是由不同病因的神经退行性疾病共有的。在一组独立的研究中，Mukhopadhayay实验室报告说，铜蓝蛋白（Cp）是大脑中主要的氧化铁酶，被活性氧（ROS）下调。由于铁具有高度的氧化还原活性，如果处理不当，它可能是ROS的主要贡献者，一旦由特定疾病过程引发，铁失衡可能通过下调主要脑氧化铁酶而被ROS延续。基于这些观察结果，我们假设ROS介导的脑特异性铁氧化酶的失调导致AD和sCJD中的铁失衡。拟议的研究将从两个具体目标来检验这一假设。在目的1中，ROS在调节特异性氧化铁酶中的作用将在AD和朊病毒疾病的细胞模型中进行研究。一旦铁氧化酶被确定，它们的调节将与Cp进行比较，Cp是由响应ROS的mRNA衰变机制调节的。随后，将确定3' UTR的最小区域和负责调节ros介导的Cp活性的结合蛋白。在目标2中，将评估ai 1中鉴定的氧化铁酶在AD和痒病感染小鼠模型中疾病进展期间的表达和活性。结果将与来自AD和sCJD病例的人脑组织进行比较，使用氧化铁酶测定和免疫组织化学作为读数。这些研究的成功完成将阐明主要脑氧化铁酶在AD和sCJD脑铁失衡中的作用，并为进一步研究PD、HD和其他与脑铁失衡相关的神经退行性疾病的脑铁失衡机制奠定基础。