Autoimmune biomarker profiling in tauopathy

tau 蛋白病中的自身免疫生物标志物分析

• 批准号: 8970227
• 负责人: IRVING E VEGA
• 金额: $ 24.79万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8970227
• 关键词: Autoimmune; biomarker; profiling; tauopathy

DESCRIPTION (provided by applicant): Tauopathies are a family of neurodegenerative disorders characterized by the intracellular aggregation of filaments predominantly composed of hyperphosphorylated microtubule-associated protein tau. This family of neurodegenerative disorders includes Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia with Parkinsonism linked to chromosome 17 and Pick disease, among others. Genetics, biochemical and neuropathological studies suggest that disruption of the biological function of tau proteins, either by mutations, hyperphosphorylation and/or aberrant protein interactions, may play a central role in the process of neurodegeneration. However, the molecular mechanisms underlying tau- mediated neurodegeneration are still poorly understood. Recently, the PI's research group has demonstrated that Amphiphysin-1 (AMPH1) protein level is significantly reduced in the tauopathy mouse model JNPL3 and AD cases. The reduction in AMPH1 protein level is associated with detection of pathological tau in terminally ill JNPL3 mice and AD. AMPH1 is a scaffold protein essential for clatherin-coated vesicle endocytosis, which plays an important role in synaptic activity and its deletion leads to cognitive impairment. Importantly, the presence of anti-AMPH1 antibodies in human serum has been correlated with a neurological disorder known as Stiff-person-syndrome. The autoimmune response that leads to the generation of anti-AMPH1 antibodies is unknown. Preliminary studies showed that terminally ill JNPL3 mice generated detectable self-AMPH1 antibodies in the serum. The detection of the self-AMPH1 antibodies correlates with reduction in the level of AMPH1 protein, suggesting that neurodegeneration in this tauopathy mouse model may lead to the disruption of self-tolerance mechanisms. Therefore, in order to characterize and validate the production of autoimmune antibodies in tau-mediated neurodegeneration the following two specific objectives will be addressed: (1) To characterize and validate the autoimmune response that lead to self-AMPH1 antibodies in tauopathies; (2) To identify autoimmune biomarkers in tau-mediated neurodegeneration. The results obtained will contribute to the identification of disease-specific protein biomarkers that could serve as diagnostic tools and for the better understanding of the pathobiology of tau-mediated neurodegeneration. Importantly, the research plan provides an opportunity to train undergraduate and graduates students on the importance of translating basic biomedical research into applied research in the quest to provide insights on diseases that afflict the general population, such as AD.

描述（由申请人提供）：Tau蛋白病是一类神经退行性疾病，其特征在于主要由过度磷酸化的微管相关蛋白tau组成的细丝的细胞内聚集。这一神经退行性疾病家族包括阿尔茨海默氏病、皮质基底节变性、进行性核上性麻痹、与 17 号染色体相关的帕金森病额颞叶痴呆和皮克病等。遗传学、生化和神经病理学研究表明，突变、过度磷酸化和/或异常蛋白质相互作用对 tau 蛋白生物学功能的破坏可能在神经变性过程中发挥核心作用。然而，tau 介导的神经变性的分子机制仍然知之甚少。最近，PI的研究小组证明，在tau蛋白病小鼠模型JNPL3和AD病例中，Amphiphysin-1（AMPH1）蛋白水平显着降低。 AMPH1 蛋白水平的降低与晚期 JNPL3 小鼠和 AD 中病理性 tau 蛋白的检测有关。 AMPH1 是网格蛋白包被的囊泡内吞作用所必需的支架蛋白，在突触活动中发挥着重要作用，其缺失会导致认知障碍。重要的是，人血清中抗 AMPH1 抗体的存在与一种称为僵人综合症的神经系统疾病有关。导致抗 AMPH1 抗体产生的自身免疫反应尚不清楚。初步研究表明，身患绝症的 JNPL3 小鼠在血清中产生了可检测到的自身 AMPH1 抗体。自身 AMPH1 抗体的检测与 AMPH1 蛋白水平的降低相关，表明该 tau 蛋白病小鼠模型中的神经变性可能导致自我耐受机制的破坏。因此，为了表征和验证 tau 介导的神经变性中自身免疫抗体的产生，将解决以下两个具体目标：（1）表征和验证 tau 病中导致自身 AMPH1 抗体的自身免疫反应； (2) 鉴定 tau 介导的神经变性中的自身免疫生物标志物。获得的结果将有助于识别疾病特异性蛋白质生物标志物，这些标志物可以作为诊断工具，并有助于更好地了解 tau 介导的神经变性的病理学。重要的是，该研究计划提供了一个机会，培训本科生和研究生，让他们认识到将基础生物医学研究转化为应用研究的重要性，以期为困扰普通人群的疾病（如 AD）提供见解。