The role of a novel tau-associated protein in neurodegeneration

描述(由申请人提供)：tauopathies是一种神经退行性疾病家族，其特征是源自过度磷酸化的微管相关蛋白tau的细丝在细胞内聚集。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、17号染色体连锁帕金森氏症(FTDP-17)的额颞部痴呆和Pick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。JNPL3是一种转基因小鼠，表达一种人类tau蛋白，携带一种突变(HTauP301L)，通常在FTDP-17的近亲中发现。早在6个月大的时候，JNPL3小鼠就会出现行为和运动缺陷，伴随着tau聚集体的积累。与人类的情况一样，JNPL3小鼠的细胞内tau聚集体是以年龄依赖和大脑区域特定的方式形成的。之前的研究由首席调查员(PI)进行，目的是在晚期疾病JNPL3小鼠中鉴定tau相关蛋白。从晚期JNPL3小鼠脑提取液中免疫沉淀tau蛋白，并对免疫沉淀蛋白进行串联质谱分析。PI鉴定了一种新的具有钙结合活性的tau相关蛋白。这种关联在AD和FTDP-17的人类颞脑裂解液中得到了验证。在此，我们将这种新的蛋白质称为Tau-EF Hand Containing Association Protein(TEA)。为了进一步了解Tau和TEA之间的联系的生理和/或病理作用，将进行以下三个方面的研究：(1)了解TEA蛋白的生理作用；(2)阐明TEA和Tau蛋白结合的分子要求；(3)了解TEA蛋白在Tau介导的神经退行性变中的作用。对该新蛋白在JNPL3小鼠和人脑中的生理和病理作用及其与tau蛋白的关系的研究可能为揭示人类tau病的分子机制提供相关信息。 公共卫生相关性：tau病是一组神经退行性疾病，其特征是微管相关蛋白tau的病理性聚集。导致tau蛋白聚集的病理事件仍不清楚。这项拟议的项目旨在表征新的tau相关蛋白TEA在tau介导的神经变性的发展和/或进展中所起的作用。

DESCRIPTION (provided by applicant): Tauopathies are a family of neurodegenerative disorders characterized by the intracellular aggregation of filaments derived from 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 (FTDP-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 mechanism underlying tau-mediated neurodegeneration is still poorly understood. The JNPL3 is a transgenic mouse that expresses a human tau protein bearing a mutation (hTauP301L) commonly found in kindred with FTDP-17. The JNPL3 mice also develop behavioral and motor deficits following the accumulation of tau aggregates as early as 6-months of age. As is the case in humans, intracellular tau aggregates in JNPL3 mice are formed in an age-dependent and brain-region specific manner. Previous studies, conducted by the principal investigator (PI), were directed toward the identification of tau-associated proteins in terminally ill JNPL3 mice. Tau proteins were immunoprecipitated from terminally ill JNPL3 mice brain extract and the immunoprecipitated proteins were subjected to tandem mass spectrometry analysis. The PI identified a novel tau-associated protein that possesses calcium-binding activity. This association was validated in human temporal brain lysate from AD and FTDP-17. Herein, we refer to this novel protein as Tau-EF hand containing Associated protein (TEA). In order to further understand the physiological and/or pathological role of the association between Tau and TEA the following three research objectives will be addressed: (1) To understand the physiological role of TEA proteins; (2) To elucidate the molecular requirements for the association between TEA and tau proteins; (3) To understand the role of TEA proteins in tau-mediated neurodegeneration. The characterization of the physiological and pathological role of this novel protein and its association with tau proteins in JNPL3 mice and human brain may provide relevant information about the molecular mechanism underlying human tauopathy. Public Health Relevance: Tauopathies are a group of neurodegenerative disorders characterized by the pathological aggregation of the microtubule-associated protein tau. The pathological events leading to the aggregation of tau proteins are still unclear. The proposed project intends to characterize the role that the novel tau-associated protein TEA plays in the development and/or progression of tau-mediated neurodegeneration.