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Role of skin prions in disease transmission and diagnostic testing of human prion disease

皮肤朊病毒在疾病传播和人类朊病毒病诊断检测中的作用

基本信息

批准号：
10490278
负责人：
QINGZHONG KONG
金额：
$ 58.6万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10490278
关键词：
Abdomen Address Age Alzheimer&apos s Disease Animal Model Animals Area Autopsy Biological Assay Biological Markers Biopsy Specimen Bovine Spongiform Encephalopathy Brain Brain Diseases Brain Injuries Cadaver Cell Extracts Chronic Wasting Disease Clinical Creutzfeldt-Jakob Syndrome Data Diagnosis Diagnostic tests Disease Dissection Epidemiology Exhibits Exposure to Freezing Future Genetic Goals Hamsters Human Hypersensitivity skin testing Iatrogenesis Iatrogenic Disease Infectious Skin Diseases Knee Knowledge Laboratories Laparotomy Light Link Measures Medical Microtus Morphology Mus Neuraxis Neurodegenerative Disorders Operative Surgical Procedures Paraffin Embedding Parkinson Disease Patients PrP Prevention Prevention strategy Prion Diseases Prions Procedures Reporting Research Risk Role Route Sampling Scrapie Skin Skin graft Source Stains Steel Surgical Instruments Symptoms Testing Time Tissue Embedding Tissues Titrations Transgenic Mice Upper Extremity Western Blotting base body system brain tissue breast surgery cell type diagnostic assay diagnostic tool disease diagnostic disease transmission disorder risk disorder subtype epidemiology study human PrP in vivo insight misfolded protein mutant pre-clinical prevent prion seeds protein misfolding cyclic amplification skin disorder transmission process

项目摘要

ABSTRACT Prions (or PrPSc) are the causal agents of fatal transmissible prion diseases including sporadic Creutzfeldt-Jakob disease (sCJD, the most common human prion disease) in humans as well as scrapie, mad cow disease and chronic wasting disease in animals. sCJD is transmissible via medical or surgical procedures due to contamination by abundant infectious prions in the brain of patients. Notably, some epidemiological studies have also associated sCJD risk with non-neurosurgeries but experimental evidence for such a link is lacking. sCJD is currently incurable. At the onset of clinical symptoms, permanent brain damages already occurred. The absence of less invasive early diagnostic tests for the disease can result in missing the critical window for future treatments, and low brain autopsy rate due to cultural constraints prevents the surveillance of sCJD that is essential for effective prevention of iatrogenic sCJD transmissions. Our recent study using the highly sensitive real-time quaking-induced conversion (RT- QuIC) assay and humanized transgenic (Tg) mice-based bioassay revealed that the skin of sCJD patients harbors infectious prions (Orrú et al., 2017). Our new preliminary results further indicate that skin PrPSc is detectable by both RT-QuIC and serial protein misfolding cyclic amplification (sPMCA) assays even at the asymptomatic stage in a prion-infected animal model. We hypothesize that skin PrPSc can be both a source of iatrogenic prion transmission and a biomarker for preclinical/premortem/postmortem diagnostic testing of prion diseases. To test for the hypothesis, the following four Aims will be pursued: (1) to quantitate infectivity of skin prions from sCJD patients, (2) to pinpoint the distribution of PrPSc within the skin, (3) to evaluate the potential of skin PrPSc as the source of iatrogenic transmission, and (4) to validate skin PrPSc as a biomarker for diagnosis of prion diseases. We expect that the proposed study will not only shed light on the potential risk of human-to-human sCJD transmission via skin prions but also establish alternative preclinical/premortem/postmortem diagnostic assays for prion diseases. Moreover, new knowledge generated from this study may apply to much more common neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases where the disease-specific misfolded proteins have been observed in the skin of respective patients.

摘要朊病毒（或PrPSc）是致命的传染性朊病毒疾病（包括散发性）的病原体。人类的克雅氏病（sCJD，最常见的人类朊病毒病）以及羊瘙痒病、疯牛病和动物慢性消耗病。sCJD可通过医疗或由于患者大脑中大量感染性朊病毒的污染，值得注意的是，一些流行病学研究也将sCJD风险与非神经外科手术联系起来，但实验证据表明，因为缺乏这样的联系。sCJD目前无法治愈。在临床症状出现时，永久性的大脑损害已经发生。缺乏针对该疾病的侵入性较小的早期诊断测试可能导致错过了未来治疗的关键窗口，由于文化限制，脑尸检率较低阻碍了对sCJD的监测，而这对于有效预防医源性sCJD至关重要传动.我们最近的研究使用高灵敏度的实时quaking-induced转换（RT- QuIC）测定和基于人源化转基因（Tg）小鼠的生物测定显示，sCJD的皮肤患者携带有传染性朊病毒（Orrú等人，2017年）。我们新的初步结果进一步表明， PrPSc可通过RT-QuIC和系列蛋白质错误折叠循环扩增（sPMCA）测定检测，在朊病毒感染的动物模型中的无症状阶段。我们假设皮肤PrPSc可以是医源性朊病毒传播的来源和临床前/死亡前/死亡后的生物标志物朊病毒疾病的诊断测试。为了检验假设，将追求以下四个目标： (1)定量sCJD患者皮肤朊病毒的感染性，（2）确定PrPSc在皮肤，（3）评估皮肤PrPSc作为医源性传播来源的潜力，以及（4）验证皮肤PrPSc作为朊病毒病诊断生物标志物我们预计，拟议的研究不仅将揭示了通过皮肤朊病毒在人与人之间传播sCJD的潜在风险，朊病毒疾病的替代临床前/死亡前/死亡后诊断测定。此外，新这项研究产生的知识可能适用于更常见的神经退行性疾病，如阿尔茨海默氏症和帕金森氏症，其中疾病特异性错误折叠蛋白质已经在各个患者的皮肤中观察到。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A comparative blind study between skin biopsy and seed amplification assay to disclose pathological α-synuclein in RBD.

DOI：
10.1038/s41531-023-00473-5
发表时间：
2023-03-04
期刊：
NPJ Parkinson's disease
影响因子：
0
作者：
Liguori R;Donadio V;Wang Z;Incensi A;Rizzo G;Antelmi E;Biscarini F;Pizza F;Zou W;Plazzi G
通讯作者：
Plazzi G

Neuroprotective effect and potential of cellular prion protein and its cleavage products for treatment of neurodegenerative disorders part II: strategies for therapeutics development.