Biology of Prion Protein and the TSE Diseases

朊病毒蛋白的生物学和 TSE 疾病

• 批准号: 9560559
• 负责人: Bruce Chesebro
• 金额: $ 104.55万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9560559
• 关键词: Adipocytes; Amyloid; Animal Diseases; Biology; Blood Vessels; Brain; Brain Injuries; Brown Fat; Cardiac Myocytes; Cell membrane; Cholesterol; Clinical; Colon; Deposition; Disease; Drug Kinetics; Effectiveness; Enteral; Euthanasia; Fatty acid glycerol esters; Follicular Dendritic Cells; Gliosis; Heart; Individual; Infection; Label; Lymphoid Tissue; Modeling; Molecular; Mus; Neurodegenerative Disorders; Neurons; Neuropathogenesis; Organ; Pathogenicity; Pathology; Peptide Hydrolases; Phagolysosome; Pharmaceutical Preparations; PrPSc Proteins; Pravastatin; Prevention strategy; Prion Diseases; Prions; Proteins; Reporting; Resistance; Scrapie; Serum; Simvastatin; Spinal Cord; Staining method; Stains; Testing; Time; Tissues; Wild Type Mouse; atorvastatin; brain cell; cell type; design; ganglion cell; human disease; improved; interstitial; macrophage; neuroinflammation; protein expression; response

Prion diseases or transmissible spongiform encephalopathies are infectious neurodegenerative diseases of humans and animals. A major feature of prion diseases is the refolding and aggregation of a normal host protein, prion protein (PrP), into a disease-associated protease-resistant form (PrPres) which may contribute to brain damage. We previously documented the molecular details of the neuroinflammatory response in brain following scrapie infection. In FY17 we treated scrapie-infected mice with statin drugs to attempt to reduce neuroinflammation and prolong survival. In previous studies treatment of scrapie-infected mice with the Type 1 statins, simvastatin or pravastatin, showed a small beneficial effect on survival time. In the current study, to increase the effectiveness of statin therapy, we treated infected mice with atorvastatin, a Type 2 statin that has improved pharmacokinetics over many Type 1 stains. Treatments with either simvastatin or pravastatin were tested for comparison. We evaluated scrapie-infected mice for PrPres accumulation, gliosis, neuroinflammation, and time until advanced clinical disease requiring euthanasia. All three statin treatments reduced total serum cholesterol 40% in mice. However, gliosis and PrPres deposition were similar in statin-treated and untreated infected mice. Time to euthanasia due to advanced clinical signs was not changed in statin-treated mice relative to untreated mice, a finding at odds with previous reports. Our studies indicate that none of the three statins tested was effective in reducing scrapie-induced neuroinflammation or neuropathogenesis. In FY17 we examined the pathology and ultrastructure of disease-induced PrPSc in organs outside the brain and spinal cord in a model where anchorless PrP is deposited as amyloid aggregates in various tissues. Amyloid PrPSc fibrils identified by immunogold-labeling were visible at high magnification in interstitial regions and around blood vessels of heart, brown fat, white fat, colon, and lymphoid tissues. PrPSc amyloid was located on and outside the plasma membranes of adipocytes in brown fat and cardiomyocytes, and appeared to invaginate and disrupt the plasma membranes of these cell types, suggesting cellular damage. In contrast, no cellular damage was apparent near PrPSc associated with macrophages in lymphoid tissues and colon, with enteric neuronal ganglion cells in colon or with adipocytes in white fat. PrPSc localized in macrophage phagolysosomes lacked discernable fibrils and might be undergoing degradation. Furthermore, in contrast to wild-type mice expressing GPI-anchored PrP, in lymphoid tissues of tg anchorless mice, PrPSc was not associated with follicular dendritic cells (FDC), and FDC did not display typical prion-associated pathogenic changes. Thus, amyloid PrPSc appeared to induce specific damage to certain cell types during prion infection of mice expressing anchorless PrP.

朊病毒病或传染性海绵状脑病是人类和动物的传染性神经退行性疾病。朊病毒疾病的一个主要特征是正常宿主蛋白朊病毒蛋白 (PrP) 重新折叠和聚集成疾病相关的蛋白酶抗性形式 (PrPres)，这可能会导致脑损伤。我们之前记录了瘙痒病感染后大脑中神经炎症反应的分子细节。 2017 财年，我们用他汀类药物治疗感染痒病的小鼠，试图减少神经炎症并延长生存期。在之前的研究中，用 1 型他汀类药物、辛伐他汀或普伐他汀治疗感染痒病的小鼠，显示出对生存时间的微小有益影响。在当前的研究中，为了提高他汀类药物治疗的有效性，我们用阿托伐他汀治疗受感染的小鼠，阿托伐他汀是一种 2 型他汀类药物，与许多 1 型他汀类药物相比，其药代动力学有所改善。对辛伐他汀或普伐他汀的治疗进行了测试以进行比较。我们评估了感染痒病的小鼠的 PrPres 积累、神经胶质增生、神经炎症以及直至出现需要安乐死的晚期临床疾病的时间。所有三种他汀类药物治疗均可使小鼠血清总胆固醇降低 40%。然而，在他汀类药物治疗和未治疗的感染小鼠中，神经胶质增生和 PrPres 沉积相似。与未治疗的小鼠相比，接受他汀类药物治疗的小鼠因晚期临床症状而实施安乐死的时间没有变化，这一发现与之前的报道不一致。我们的研究表明，所测试的三种他汀类药物均不能有效减少瘙痒病引起的神经炎症或神经发病机制。 在 2017 财年，我们在一个模型中检查了大脑和脊髓以外的器官中疾病诱发的 PrPSc 的病理学和超微结构，其中无锚定的 PrP 以淀粉样蛋白聚集体的形式沉积在各种组织中。通过免疫金标记鉴定的淀粉样蛋白 PrPSc 原纤维在心脏、棕色脂肪、白色脂肪、结肠和淋巴组织的间质区域和血管周围在高放大倍数下可见。 PrPSc 淀粉样蛋白位于棕色脂肪和心肌细胞的脂肪细胞质膜之上和之外，并且似乎内陷并破坏这些细胞类型的质膜，表明细胞损伤。 相比之下，在与淋巴组织和结肠中的巨噬细胞、结肠中的肠神经元神经节细胞或白色脂肪中的脂肪细胞相关的PrPSc附近没有明显的细胞损伤。位于巨噬细胞吞噬溶酶体中的 PrPSc 缺乏可辨别的原纤维，可能正在经历降解。此外，与表达GPI锚定PrP的野生型小鼠相比，在tg锚定小鼠的淋巴组织中，PrPSc与滤泡树突状细胞（FDC）无关，并且FDC没有表现出典型的朊病毒相关致病变化。因此，在表达无锚定 PrP 的小鼠感染朊病毒期间，淀粉样蛋白 PrPSc 似乎会诱导对某些细胞类型的特异性损伤。