Cysteine-Independent Inhibition of Alzheimer's Disease-like Paired Helical Filament Assembly by Leuco-Methylthioninium (LMT)

Youssra K. Al-Hilaly; Saskia J. Pollack; Janet E. Rickard; Michael Simpson; Ana-Caroline Raulin; Thomas Baddeley; Pascale Schellenberger; John M.D. Storey; Charles R. Harrington; Claude M. Wischik; Louise C. Serpell

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Cysteine-Independent Inhibition of Alzheimer's Disease-like Paired Helical Filament Assembly by Leuco-Methylthioninium (LMT)

机译：用甲基甲基氨基尼（LMT）的半胱氨酸抑制阿尔茨海默氏症的疾病状纤维丝组件

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Alzheimer's disease is a tauopathy characterized by pathological fibrillization of tau protein to form the paired helical filaments (PHFs), which constitute neurofibrillary tangles. The methylthioninium (MT) moiety reverses the proteolytic stability of the PHF core and is in clinical development for treatment of Alzheimer's disease in a stable reduced form as leuco-MT. It has been hypothesized that MT actsviaoxidation of cysteine residues, which is incompatible with activity in the predominantly reducing environment of living cells. We have shown recently that the PHF-core tau unit assembles spontaneouslyin vitroto form PHF-like filaments. Here we describe studies using circular dichroism, SDS-PAGE, transmission electron microscopy and site-directed mutagenesis to elucidate the mechanism of action of the MT moiety. We show that MT inhibitory activity is optimal in reducing conditions, that the active moiety is the reduced leuco-MT form of the molecule and that its mechanism of action is cysteine independent.

机译：阿尔茨海默病是一种特征，其特征是Tau蛋白的病理原纤维化，形成成对的螺旋丝细丝（PHF），构成神经原纤维缠结。甲基硫氨基鎓（MT）部分逆转了PHF核心的蛋白水解稳定性，并且在临床开发中以稳定的降低形式治疗阿尔茨海默病，为Leuco-mt。已经假设了半胱氨酸残基的MT Actsvia氧化，其与主要减少活细胞环境中的活性不相容。我们最近显示了PHF-Core Tau单位组装自来组织vitroto形式的pHF样细丝。在这里，我们描述了使用圆形二色性，SDS-PAGE，透射电子显微镜和定向诱变的研究，以阐明MT部分的作用机制。我们表明，在还原条件下，MT抑制活性是最佳的，所以活性部分是分子的降低的Leuco-Mt形式，并且其作用机制是半胱氨酸的。

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来源
《Journal of Molecular Biology》 |2018年第21期|共13页
作者
Youssra K. Al-Hilaly; Saskia J. Pollack; Janet E. Rickard; Michael Simpson; Ana-Caroline Raulin; Thomas Baddeley; Pascale Schellenberger; John M.D. Storey; Charles R. Harrington; Claude M. Wischik; Louise C. Serpell;
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作者单位

Dementia Research Group School of Life Sciences University of Sussex;

Dementia Research Group School of Life Sciences University of Sussex;

Institute of Medicine Medical Sciences and Nutrition University of Aberdeen;

TauRx Therapeutics Ltd. Aberdeen AB25 2ZP;

Dementia Research Group School of Life Sciences University of Sussex;

TauRx Therapeutics Ltd. Aberdeen AB25 2ZP;

Dementia Research Group School of Life Sciences University of Sussex;

TauRx Therapeutics Ltd. Aberdeen AB25 2ZP;

Institute of Medicine Medical Sciences and Nutrition University of Aberdeen;

Institute of Medicine Medical Sciences and Nutrition University of Aberdeen;

Dementia Research Group School of Life Sciences University of Sussex;

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正文语种 eng
中图分类分子生物学;
关键词
tau protein; methylthioninium; hydromethylthionine; neurofibrillary tangles; circular dichroism;

机译：Tau蛋白;甲基硫氨酸;氢甲基硫氨酸;神经纤维纤维缠结;圆形二分;

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1. Cysteine-Independent Inhibition of Alzheimer's Disease-like Paired Helical Filament Assembly by Leuco-Methylthioninium (LMT) [J] . Youssra K. Al-Hilaly, Saskia J. Pollack, Janet E. Rickard, Journal of Molecular Biology . 2018,第21期

机译：用甲基甲基氨基尼（LMT）的半胱氨酸抑制阿尔茨海默氏症的疾病状纤维丝组件
2. Expression of an altered form of tau in Sf9 insect cells results in the assembly of polymers resembling Alzheimer's paired helical filaments. [J] . Gomez Ramos A, Abad X, Lopez Fanarraga M, Brain research . 2004,第1a2期

机译：在Sf9昆虫细胞中tau改变形式的表达导致聚合物的组装，类似于阿尔茨海默氏症的成对螺旋丝。
3. Assembly of T protein into Alzheimer paired helical filaments depends on a local sequence motif ~(so6VQlVYK~311) forming beta structure [J] . M. von Bergen, P. Friedhoff, J. Biernat Proceedings of the National Academy of Sciences of the United States of America . 2000,第10期

机译：T蛋白组装成阿尔茨海默氏症成对的螺旋状细丝取决于形成β结构的局部序列基序〜（so6VQlVYK〜311）
4. Grape Seed Polyphenolic Extract as a Potential Therapeutic Compound in Tau-Mediated Neurodegenerative Disorders. Electron Microscopy Analysis of Paired Helical Filaments [C] . I. Santa-Maria Microscopy and microanalysis.;Microscopy and microanalysis. . -1

机译：葡萄籽多酚提取物作为Tau介导的神经退行性疾病的潜在治疗化合物。螺旋丝对的电子显微镜分析
5. Practicum Three, April 14, 2000. Ruthenium-based luminescence imaging fiber chemical sensors. Practicum Two, November 2, 1998. Implementation of improved software for particulate contamination control in integrated circuit manufacturing. Practicum One, September 29, 1997. Characterization of the paired helical filament glycolipid. [D] . Stokes, Harold Wayne, Jr. 2000

机译：实习三，2000年4月14日。基于钌的发光成像纤维化学传感器。实习二，1998年11月2日。在集成电路制造中实施改进的用于颗粒物污染控制的软件。实践一，1997年9月29日。配对的螺旋丝糖脂的表征。
6. Assembly of τ protein into Alzheimer paired helical filaments depends on a local sequence motif (306VQIVYK311) forming β structure [O] . M. von Bergen, P. Friedhoff, J. Biernat, 2000

机译：τ蛋白组装成阿尔茨海默氏症成对的螺旋细丝取决于形成β结构的局部序列基序（306VQIVYK311）
7. Cysteine-Independent Inhibition of Alzheimer's Disease-like Paired Helical Filament Assembly by Leuco-Methylthioninium (LMT) [O] . Youssra K. Al-Hilaly, Saskia J. Pollack, Janet E. Rickard, 2018

机译：用甲基甲基氨基尼（LMT）的半胱氨酸抑制阿尔茨海默氏症的疾病状纤维丝组件

Cysteine-Independent Inhibition of Alzheimer's Disease-like Paired Helical Filament Assembly by Leuco-Methylthioninium (LMT)

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