Molecular Basis of Iron Imbalance in sCJD Brain and CSF

sCJD 脑和脑脊液中铁失衡的分子基础

• 批准号: 8302810
• 负责人: Neena Singh
• 金额: $ 19.63万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8302810
• 关键词: Affect; Alzheimer' s Disease; Animal Model; Animals; Autopsy; Biological Markers; Blood; Blood Cells; Blood Circulation; Brain; Carrier Proteins; Cells; Cerebrospinal Fluid; Ceruloplasmin; Cessation of life; Chronic Wasting Disease; Creutzfeldt-Jakob Syndrome; Data; Dementia; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Progression; Evaluation; Ferritin; Goals; Grant; Hamsters; Homeostasis; Human; In Transferrin; Individual; Infection; Iron; Lumbar spinal cord structure; Modeling; Molecular; Monitor; Mus; Nature; Nerve Degeneration; Neurons; Oxidation-Reduction; Parkinson Disease; Pathogenesis; Pathology; Peripheral; Phenotype; PrPSc Proteins; Prion Diseases; Prions; Process; Protein Isoforms; Proteins; Publishing; Radiolabeled; Regulation; Relative (related person); Risk; Sampling; Scrapie; Sensitivity and Specificity; Signal Transduction; Site; Tail; Testing; Time; Tissues; Transferrin; Transferrin Receptor; Veins; base; cervid; diagnostic accuracy; disease transmission; end stage disease; improved; iron deficiency; neurotoxicity; peripheral blood; prevent; prognostic; protein complex; radiotracer; response; therapeutic development; uptake

DESCRIPTION (provided by applicant): Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal prion disorder of humans that escapes detection until autopsy. The principal cause of neurotoxicity in this and other prion disorders is accumulation of PrP-scrapie (PrPSc), a ¿-sheet rich isoform of prion protein (PrPC) in the brain parenchyma. Participation of other processes is suspected, but their mechanism of action is unclear. Emerging evidence indicates that imbalance of iron homeostasis is a consistent feature of affected brains, implicating redox-iron in disease associated neurotoxicity. Unlike Alzheimer's disease (AD) where diseased brains accumulate iron, brains from sCJD and scrapie infected animal models reveal a phenotype of 'functional' iron deficiency as suggested by a significant increase in the iron uptake protein transferrin (Tf) despite minimal change in brain iron levels. Moreover, Tf levels increase with disease progression in direct correlation with PrPSc, suggesting a cause and effect relationship with disease pathogenesis. Surprisingly, instead of a compensatory increase, levels of Tf are significantly decreased in the cerebrospinal-fluid (CSF) of sCJD cases much before end-stage disease, indicating mis-regulation of signaling between iron starved brain parenchymal cells and the blood-brain and brain-CSF barriers involved in iron transport from the peripheral circulation to the brain and secretion of brain Tf respectively. Based on these observations, we hypothesize that sCJD associated disruption of brain iron regulation causes specific changes in CSF levels of iron management proteins that correlate with disease progression, providing disease specific biomarker(s) for sCJD. Two specific aims are proposed to test this hypothesis. In aim 1, the mechanism underlying decreased CSF Tf in sCJD brains will be explored using scrapie infected mice as models. Specifically, change in brain iron levels during scrapie infection, correlation between brain iron and PrPSc levels, and change in iron transport from the peripheral circulation to the brain will be monitored by tracking transport of radiolabeled iron (59Fe) from the tail vein to the brain and CSF compartments during prion disease progression. 59Fe counts in the brain and CSF will be correlated with levels of iron management proteins to evaluate the integrity of brain iron signaling mechanisms. In aim 2, the specificity and sensitivity of CSF Tf and other iron management proteins, the 'new' biomarkers, will be compared with 'current' surrogate CSF biomarkers of sCJD. The accuracy of new biomarkers in differentiating sCJD from rapidly progressive dementia and AD, potentially treatable causes of dementias often misdiagnosed as sCJD, will be emphasized. The prognostic reliability of new biomarkers will be assessed in CSF samples collected at different time points during disease progression from scrapie infected mice and Chronic Wasting Disease infected cervids, and the earliest time-point of a significant change will be identified. Successful completion of these studies will improve our understanding of the mechanism leading to decreased CSF Tf in sCJD, and facilitate the development of a rapid, specific, and sensitive pre-mortem diagnostic test for sCJD. PUBLIC HEALTH RELEVANCE: Prion disorders are a group of invariably fatal neurodegenerative conditions of humans and animals that are sporadic and infectious in nature. Currently, the only reliable diagnostic test for these disorders is post- mortem, posing a risk of disease transmission from undiagnosed cases to healthy individuals. Our data indicate that the iron transport protein transferrin is decreased in the cerebrospinal fluid (CSF) of sporadic Creutzfeldt-Jakob disease (sCJD) cases. In this application we will investigate the underlying mechanism of this change, and whether CSF Tf and other iron management proteins can be used as a diagnostic biomarker for sCJD.

描述(申请人提供)：散发性克雅氏病(SCJD)是人类的一种致命的普恩疾病，直到尸检时才被发现。PrP-scrapie(PrPSc)是PrP-scrapie(PrPSc)在脑实质中堆积的主要原因，PrP-scrapie是一种富含PrPC的异构体。其他进程的参与值得怀疑，但它们的作用机制尚不清楚。新的证据表明，铁稳态的失衡是受影响大脑的一贯特征，这表明氧化还原铁与疾病相关的神经毒性有关。与阿尔茨海默病(AD)不同，阿尔茨海默病(AD)患者的大脑积聚了铁，而sCJD和瘙痒病感染动物模型的大脑显示出一种“功能性”缺铁的表型，这表明尽管脑铁水平变化很小，但铁摄取蛋白转铁蛋白(Tf)显著增加。此外，Tf水平随着疾病的进展而增加，与PrPSc直接相关，提示与疾病的发病机制存在因果关系。令人惊讶的是，sCJD患者脑脊液(CSF)中Tf水平非但没有代偿性增加，反而在终末期疾病发生之前就显著降低，这表明铁缺乏的脑实质细胞与血-脑和脑-脑脊液屏障之间的信号调节错误，这些屏障分别参与了铁从外周循环到脑的运输和脑Tf的分泌。基于这些观察结果，我们假设SCJD相关的脑铁调节障碍导致与疾病进展相关的脑脊液中铁管理蛋白水平的特异性变化，从而为SCJD提供疾病特异性生物标志物(S)。为了检验这一假说，本文提出了两个具体目标。目的1以瘙痒病感染小鼠为模型，探讨sCJD脑内脑脊液转铁蛋白降低的机制。具体地说，瘙痒病感染期间脑铁水平的变化，脑铁和PrPSc水平之间的相关性，以及从外周循环到大脑的铁运输的变化，将通过跟踪普恩病毒疾病进展期间放射性标记铁(59Fe)从尾静脉到脑和脑脊液隔室的运输来监测。脑和脑脊液中的59Fe计数将与铁管理蛋白的水平相关，以评估脑铁信号机制的完整性。在目标2中，新的生物标记物--脑脊液转铁蛋白和其他铁管理蛋白的特异性和敏感性将与sCJD的脑脊液替代生物标记物进行比较。将强调新的生物标记物在区分sCJD与快速进行性痴呆和AD方面的准确性，这些可能导致痴呆的原因经常被误诊为sCJD。新生物标志物的预后可靠性将在疾病进展过程中不同时间点收集的脑脊液样本中进行评估，这些样本来自瘙痒病感染的小鼠和慢性消耗性疾病感染的宫颈，并将确定显著变化的最早时间点。成功完成这些研究将改善我们的 了解sCJD患者脑脊液转铁蛋白降低的机制，并促进sCJD快速、特异和灵敏的死前诊断试验的开发。 与公共卫生相关：Pron疾病是一组总是致命的人类和动物的神经退行性疾病，本质上是散发性和传染性的。目前，对这些疾病唯一可靠的诊断测试是尸检，这带来了疾病从未诊断病例传播给健康人的风险。我们的数据表明，散发性克雅氏病(SCJD)患者脑脊液(CSF)中铁转运蛋白降低。在这项应用中，我们将研究这种变化的潜在机制，以及脑脊液转铁蛋白和其他铁管理蛋白是否可以作为sCJD的诊断生物标志物。