Autoimmune biomarker profiling in tauopathy

描述(申请人提供)：tauopathies是一种神经退行性疾病家族，其特征是细胞内的细丝聚集，主要由过度磷酸化的微管相关蛋白tau组成。这一家族的神经退行性疾病包括阿尔茨海默病、皮质基底膜退行性变、进行性核上性瘫痪、与17号染色体连锁的帕金森氏症的额颞痴呆和皮克病等。遗传学、生物化学和神经病理学研究表明，tau蛋白生物学功能的破坏，无论是通过突变、过度磷酸化和/或异常的蛋白质相互作用，都可能在神经退行性变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JNPL3和AD模型小鼠中，两栖动物蛋白-1(AMPH1)的蛋白水平显著降低。AMPH1蛋白水平的降低与绝症JNPL3小鼠和AD中病理tau的检测有关。AMPH1是一种骨架蛋白，对包被Clatherin的囊泡内吞作用至关重要，它在突触活动中起重要作用，其缺失会导致认知功能障碍。重要的是，人类血清中抗AMPH1抗体的存在与一种被称为僵人综合征的神经疾病有关。导致产生抗AMPH1抗体的自身免疫反应尚不清楚。初步研究表明，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，表明这种互补性小鼠模型中的神经退变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，将解决以下两个特定目标：(1)表征和验证tau介导的神经变性中导致自身AMPH1抗体的自身免疫反应；(2)确定tau介导的神经变性中的自身免疫生物标志物。所获得的结果将有助于识别可作为诊断工具的疾病特异性蛋白生物标志物，并有助于更好地理解tau介导的神经退行性变的病理生物学。重要的是，研究计划提供了培训本科生和研究生的机会，使他们了解将基础生物医学研究转化为应用研究的重要性，以寻求对困扰普通人群的疾病(如阿尔茨海默病)提供见解。

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.