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（由申请方提供）：散发性克雅氏病（sCJD）是一种致命的人类朊病毒疾病，在尸检前无法检测到。在这种和其他朊病毒疾病中神经毒性的主要原因是朊病毒瘙痒症（PrPSc）的积累，朊病毒蛋白（PrPC）在脑实质中的一种富含半片层的同种型。怀疑其他进程也参与其中，但其作用机制尚不清楚。新出现的证据表明，铁稳态的不平衡是受影响的大脑的一致特征，涉及氧化还原铁与疾病相关的神经毒性。与阿尔茨海默病（AD）不同，患病的大脑积累铁，来自sCJD和羊瘙痒病感染的动物模型的大脑揭示了“功能性”铁缺乏的表型，如铁摄取蛋白转铁蛋白（Tf）的显著增加所表明的，尽管脑铁水平变化极小。此外，Tf水平随着疾病进展而增加，与PrPSc直接相关，表明与疾病发病机制的因果关系。令人惊讶的是，sCJD病例的脑脊液（CSF）中Tf水平在终末期疾病之前显著降低，而不是代偿性增加，这表明铁饥饿的脑实质细胞与分别涉及铁从外周循环转运到脑和脑Tf分泌的血脑和脑CSF屏障之间的信号传导的错误调节。基于这些观察结果，我们假设sCJD相关的脑铁调节的破坏引起与疾病进展相关的CSF铁管理蛋白水平的特定变化，为sCJD提供疾病特异性生物标志物。提出了两个具体目标来检验这一假设。在目的1中，将使用羊瘙痒病感染的小鼠作为模型来探索sCJD脑中CSF Tf降低的潜在机制。具体而言，通过跟踪朊病毒疾病进展期间放射性标记铁（59 Fe）从尾静脉向脑和CSF隔室的转运，监测羊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铁从外周循环向脑转运的变化。脑和CSF中的59 Fe计数将与铁管理蛋白的水平相关，以评估脑铁信号传导机制的完整性。在目标2中，将CSF Tf和其他铁管理蛋白（“新”生物标志物）的特异性和灵敏度与sCJD的“当前”替代CSF生物标志物进行比较。新的生物标志物在区分sCJD与快速进展性痴呆和AD中的准确性，痴呆的潜在可治疗原因经常被误诊为sCJD，将被强调。将在疾病进展期间的不同时间点从羊瘙痒病感染的小鼠和慢性消耗病感染的鹿收集的CSF样品中评估新生物标志物的预后可靠性，并将鉴定显著变化的最早时间点。成功完成这些研究将提高我们的 了解导致sCJD中CSF Tf降低的机制，并促进sCJD的快速，特异性和敏感性的死前诊断试验的发展。 公共卫生相关性：朊病毒疾病是一组人类和动物的不可避免的致命性神经退行性疾病，具有散发性和传染性。目前，对这些疾病的唯一可靠诊断测试是死后检查，这带来了疾病从未确诊病例传播到健康个体的风险。我们的数据表明，铁转运蛋白转铁蛋白减少，在脑脊液（CSF）的散发性克雅氏病（sCJD）的情况下。在本申请中，我们将研究这种变化的潜在机制，以及CSF Tf和其他铁管理蛋白是否可以用作sCJD的诊断生物标志物。