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首页> 外文期刊>Nature >Cystathionine γ- lyase deficiency mediates neurodegeneration in Huntington's disease
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Cystathionine γ- lyase deficiency mediates neurodegeneration in Huntington's disease

机译：胱硫醚γ-裂合酶缺乏介导亨廷顿舞蹈病的神经变性

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摘要

Huntington's disease is an autosomal dominant disease associated with a mutation in the gene encoding huntingtin (Htt) leading to expanded polyglutamine repeats of mutant Htt (mHtt) that elicit oxidative stress, neurotoxicity, and motor and behavioural changes. Huntington's disease is characterized by highly selective and profound damage to the corpus striatum, which regulates motor function. Striatal selectivity of Huntington's disease may reflect the striatally selective small G protein Rhes binding to mHtt and enhancing its neurotoxicity. Specific molecular mechanisms by which mHtt elicits neurodegeneration have been hard to determine. Here we show a major depletion of cystathionine γ-lyase (CSE), the biosynthetic enzyme for cysteine, in Huntington's disease tissues, which may mediate Huntington's disease pathophysiology. The defect occurs at the transcriptional level and seems to reflect influences of mHtt on specificity protein 1, a transcriptional activator for CSE. Consistent with the notion of loss of CSE as a pathogenic mechanism, supplementation with cysteine reverses abnormalities in cultures of Huntington's disease tissues and in intact mouse models of Huntington's disease, suggesting therapeutic potential.
机译：亨廷顿舞蹈病是一种常染色体显性遗传疾病，与亨廷顿蛋白（Htt）编码基因突变相关，导致突变型Htt（mHtt）的聚谷氨酰胺重复序列扩大，从而引起氧化应激，神经毒性以及运动和行为改变。亨廷顿氏病的特征是纹状体高度选择性和严重受损，从而调节运动功能。亨廷顿氏病的纹状体选择性可能反映了纹状体选择性小G蛋白Rhes与mHtt结合并增强其神经毒性。很难确定mHtt引起神经变性的具体分子机制。在这里，我们显示了亨廷顿氏病组织中半胱氨酸生物分解酶胱硫醚γ-裂合酶（CSE）的大量消耗，这可能介导了亨廷顿氏病的病理生理。该缺陷发生在转录水平，似乎反映了mHtt对特异性蛋白1（CSE的转录激活因子）的影响。与CSE丧失是一种致病机理的观念相一致，补充半胱氨酸可以逆转亨廷顿氏病组织培养物中和亨廷顿氏病完整小鼠模型中的异常现象，表明具有治疗潜力。

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  • 来源
    《Nature》 |2014年第7498期|96-100|共5页
  • 作者

    Bindu D. Paul; Juan I. Sbodio; Risheng Xu; M. Scott Vandiver; Jiyoung Y. Cha; Adele M. Snowman; Solomon H. Snyder;

  • 作者单位

    The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA ,Department of Pharmacology and Molecular Sciences, John Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA ,Department of Pharmacology and Molecular Sciences, John Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA ,Department of Pharmacology and Molecular Sciences, John Hopkins University School of Medicine, Baltimore, Maryland 21205, USA ,Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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