Investigation of mechanism of tauopathy and application for clinical diagnosis

tau蛋白病机制研究及临床诊断应用

• 批准号: 13670667
• 负责人: MORI Hideo
• 金额: $ 2.18万
• 依托单位: Juntendo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670667/
• 关键词: Tau protein; Dementia; Parkinsonism; Progressive supranuclear palsy; Corticobasal degeneration; Tau gene; Tau isoform; CSF; タウ; 遺伝子変異; タウオパチー; 定量的RT-PCR法; 前頭側頭型痴呆; mRNA; RT-PCR

1)We have made an antibody which selectively recognized the four-repeat tau protein. (4R-tau). Using this antibody, we examined the brain tissue of the patients with progressive supranuclear palsy (PSP) and demonstrated that tau-positive tufted astrocyte, pretangle and theads were composed of 4R-tau and 4R-tau-positive tufted astrocytes were not reactive for anti-GFAP antibody.2)Using the antibody for 4R-tau, we are establishing the method for measure of 4R-tau in cerebrospinal fluid. The method is based on ELISA.3)We have found a new mutation of the tau gene (L266V) in a familial tauopathy (frontotemporal dementia and parkinsonism linked to chromosome 17) and we examined the brain of a patient of this kindred and demonstrated Pick body-like inclusions and unique tau-positive astrocytes.4)We have reported two patients of the two families with P301L tau mutation, who showed different phenotype. Their genotypes of the tau gene were different at three sites, and the studies suggested they do not share a common founder for P301L mutation and either of the two less prevalent genotypes observed in patient 2 may be the factor to modify the phenotype of P301L mutation into those unusual clinical features with prominent parkinsonism.5)Using quantitative RT-PCR method, we investigated the expression level of tau mRNA isoforms in the frontal cortex and globus pallidus of patients with PSP and corticobasal degeneration (CBD). The 4R/3R ratios in frontal cortices of CBD and globus pallidus of PSP and CBD were significantly higher than the control. There was no correlation between the expression patterns of tau mRNA isoforms and p-tau accumulation. Our findings suggest that neurodegeneration of PSP and CBD could be regulated by alternative splicing of tau mRNA to yield high 4R/3R ratio but also other factors such as post-transcriptional or translational modifications may play a role in the pathogenesis of specific neurodegeneration in PSP and CBD.

1）我们制作了一种抗体，该抗体有选择地识别四重tau蛋白。 （4r-tau）。使用该抗体，我们检查了进行性次脑性瘫痪（PSP）患者的脑组织，并证明Tau阳性簇状的星形胶质细胞，伪造和斜虫由4R-TAU和4R-TAU和4R-TAU阳性的簇生组成。脑脊液中的4R-TAU。该方法基于ELISA。3）我们在家族性的tauopathy中发现了tau基因（L266V）的新突变（额颞痴呆和帕金森氏症与17号染色​​体相关），我们检查了这个善良的和表现出的the tau pos posive posive posive posiver tau two two two tworcy.4）。突变，表现出不同的表型。它们的Tau基因的基因型在三个位点不同，研究表明，它们不共享P301l突变的共同创始人，并且在患者2中观察到的两个较少普遍的基因型中的任何一个都可能是将P301L突变的表型在使用量子级别的parkinsiss.5级别的情况下。 PSP和皮质性肥大变性（CBD）患者的额叶皮层和果胶pallidus。 PSP和CBD的CBD和Globus Pallidus的额叶皮层中的4R/3R比显着高于对照。 Tau mRNA同工型的表达模式与P-TAU积累之间没有相关性。我们的发现表明，PSP和CBD的神经退行性因素可以通过TAU mRNA的替代剪接来调节以产生高4R/3R比，但其他因素（例如转录后或翻译修饰）可能在PSP和CBD中特定神经变性的发病机理中起作用。

项目成果

Takanashi, M: "Mixed multiple system atrophy and progressive supranuclear palsy : a clinical and pathological report of one case"Acta Neuropathol. 103. 82-87 (2002)

Takanashi, M：“混合性多系统萎缩和进行性核上性麻痹：一例临床和病理报告”Acta Neuropathol。

Kobayashi T, 0 Hasegawa M, Umeda Y, Motoi Y, Takanashi M, Yasuhara M, Anno M, Mizuno Y, Mori H: "A novel L266V mutation of the tau gene causes frontotemporal dementia with a unique tau pathology."Ann Neurol. 53・1. 133-137

Kobayashi T、0 Hasekawa M、Umeda Y、Motoi Y、Takanashi M、Yasuhara M、Anno M、Mizuno Y、Mori H：“tau 基因的一种新型 L266V 突变导致具有独特 tau 病理学的额颞叶痴呆。”Ann Neurol。 53・1。133-137

Kobayashi T, O Hasegawa M, Umeda et al.: "A novel L266V mutation of the tau gene causes frontotemporal dementia with a unique tau pathology"Ann Neurol. 53・1. 133-137 (2003)

Kobayashi T、O Hasekawa M、Umeda 等：“tau 基因的新型 L266V 突变导致具有独特 tau 病理学的额颞叶痴呆”Ann Neurol 53・1（2003）。

Kobayashi, T: "Contrasting genotypes of the tau gene in two phenotypically distinct patients with P301L mutation of frontotemporal dementia and parkinsonism linked to chromosome"Journal of Neurology. 249. 669-675 (2002)

Kobayashi, T：“对比两名表型不同的额颞叶痴呆 P301L 突变和与染色体相关的帕金森病患者的 tau 基因基因型”《神经病学杂志》。

Kobayashi T, O Hasegawa M, Umeda et al.: "A novel L266V mutation of the tau causes frontotemporal dementia with a unique tau pathology"Ann Neurol. 53. 133-137 (2003)

Kobayashi T、O Hasekawa M、Umeda 等人：“tau 蛋白的一种新型 L266V 突变会导致具有独特 tau 蛋白病理学的额颞叶痴呆”Ann Neurol。