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（由申请人提供）：散发性克雅氏病（sCJD）是一种人类致命的朊病毒病，直到尸检才被发现。这种和其他朊病毒病的神经毒性的主要原因是 PrP-痒病（PrPSc）的积累。 ¿大脑实质中富含朊病毒蛋白 (PrPC) 的亚型被怀疑参与了其他过程，但其作用机制尚不清楚，新出现的证据表明，铁稳态失衡是受影响大脑的一个一致特征，这与氧化还原铁有关。与疾病相关的神经毒性不同，阿尔茨海默病（AD）患病的大脑会积聚铁，而慢性雅氏病和瘙痒病感染动物模型的大脑则显示出“功能性”缺铁的表型。尽管脑铁水平变化很小，但铁摄取蛋白转铁蛋白 (Tf) 显着增加，此外，Tf 水平随疾病进展而增加，与 PrPSc 直接相关，这表明与疾病发病机制存在因果关系。在代偿性增加的过程中，早在疾病终末期之前，sCJD 病例的脑脊液 (CSF) 中 Tf 水平就显着降低，表明缺铁脑实质细胞之间的信号传导存在错误调节血脑屏障和脑脊液屏障分别参与铁从外周循环到大脑的转运和脑 Tf 的分泌。基于这些观察，我们认为与 sCJD 相关的脑铁调节破坏会导致脑脊液水平的特定变化。与疾病进展相关的铁管理蛋白，为 sCJD 提供疾病特异性生物标志物。在目标 1 中，将使用痒病感染来探索 sCJD 大脑中 CSF Tf 降低的机制。具体而言，将通过追踪尾部放射性标记铁 (59Fe) 的转运来监测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转运的变化。在朊病毒疾病进展过程中，将脑和脑脊液中的 59Fe 计数与铁管理蛋白的水平相关联，以评估脑铁信号传导机制的完整性。在目标 2 中，脑脊液 Tf 和脑脊液的特异性和敏感性。其他铁管理蛋白，即“新”生物标志物，将与“当前”的 SCJD 替代 CSF 生物标志物进行比较。新生物标志物在区分 SCJD 与快速进展性痴呆和 AD（经常被误诊为 SCJD 的痴呆症的潜在可治疗原因）方面的准确性将得到提高。需要强调的是，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，这些样本来自痒病感染的小鼠和慢性消耗性疾病感染的小鼠。 cervids，并且将确定重大变化的最早时间点，成功完成这些研究将改善我们的情况。 了解导致 sCJD 脑脊液 Tf 降低的机制，并促进开发快速、特异且灵敏的 sCJD 死前诊断测试。 公共卫生相关性：朊病毒病是人类和动物的一组总是致命的神经退行性疾病，具有散发性和传染性，目前，对这些疾病唯一可靠的诊断测试是死后检测，存在未确诊病例传播疾病的风险。我们的数据表明，散发性克雅氏病的脑脊液 (CSF) 中铁转运蛋白转铁蛋白减少。在本申请中，我们将研究这种变化的潜在机制，以及脑脊液 Tf 和其他铁管理蛋白是否可以用作 sCJD 的诊断生物标志物。