The role of a novel tau-associated protein in neurodegeneration

描述（由申请人提供）：tau病是一类神经退行性疾病，其特征是微管相关蛋白tau过度磷酸化引起的纤维在细胞内聚集。这一神经退行性疾病家族包括阿尔茨海默病、皮质基底变性、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（FTDP-17）和皮克病等。遗传学、生物化学和神经病理学研究表明，tau蛋白的生物学功能的破坏，无论是通过突变、过度磷酸化和/或异常的蛋白质相互作用，都可能在神经变性过程中发挥核心作用。然而，tau介导的神经退行性变的分子机制仍然知之甚少。JNPL3是一种转基因小鼠，表达携带突变（hTauP301L）的人类tau蛋白，通常在FTDP-17的亲缘关系中发现。JNPL3小鼠早在6个月大时就会出现tau聚集物积累后的行为和运动缺陷。与人类的情况一样，JNPL3小鼠的细胞内tau聚集体以年龄依赖性和脑区域特异性的方式形成。先前的研究是由首席研究员（PI）进行的，旨在鉴定身患绝症的JNPL3小鼠中的tau相关蛋白。从绝症JNPL3小鼠脑提取物中免疫沉淀Tau蛋白，并对免疫沉淀蛋白进行串联质谱分析。PI发现了一种具有钙结合活性的新型tau相关蛋白。这种关联在AD和FTDP-17的人类颞叶脑裂解液中得到证实。在这里，我们将这种新蛋白称为Tau-EF含手相关蛋白（TEA）。为了进一步了解Tau蛋白与TEA之间关联的生理和/或病理作用，将解决以下三个研究目标：(1)了解TEA蛋白的生理作用；(2)阐明TEA与tau蛋白关联的分子要求；(3)了解TEA蛋白在tau介导的神经退行性变中的作用。该新蛋白在JNPL3小鼠和人脑中的生理和病理作用及其与tau蛋白的关联的表征可能为人类tau病的分子机制提供相关信息。

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.