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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Regional rescue of spinocerebellar ataxia type 1 phenotypes by 14-3-3ε haploinsufficiency in mice underscores complex pathogenicity in neurodegeneration
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Regional rescue of spinocerebellar ataxia type 1 phenotypes by 14-3-3ε haploinsufficiency in mice underscores complex pathogenicity in neurodegeneration

机译：通过14-3-3ε单倍剂量不足对小鼠脊髓小脑共济失调1型表型的区域性抢救强调了神经变性的复杂致病性

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摘要

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a CAG repeat encoding a polyglutamine tract in Ataxin-1 (ATXN1). Both WT and mutant ATXN1 interact with 14-3-3 proteins, and 14-3-3 overexpression stabilizes ATXN1 levels in cells and increases ATXN1 toxicity in flies. To determine whether reducing 14-3-3 levels might mitigate SCA1 pathogenesis, we bred Sca7~154Q/+ mice to mice lacking one allele of 14-3-3ε. 14-3-3ε haploinsufficiency rescued cerebellar pathology and motor phenotypes but, surprisingly, not weight loss, respiratory dysfunction, or premature lethality. Biochemical studies revealed that reducing 14-3-3ε levels exerted different effects in two brain regions especially vulnerable in SCA1:Although diminishing levels of both WT and mutant ATXN1 in the cerebellum, 14-3-3ε haploinsufficiency did not alter ATXN1 levels in the brainstem. Furthermore, 14-3-3ε haploinsufficiency decreased the incorporation of expanded ATXN1 into its large toxic complexes in the cerebellum but not in the brainstem, and the distribution of ATXN1's small and large native complexes differed significantly between the two regions. These data suggest that distinct pathogenic mechanisms operate in different vulnerable brain regions, adding another level of complexity to SCA1 pathogenesis.
机译：脊髓小脑共济失调1型（SCA1）是一种神经退行性疾病，由Ataxin-1（ATXN1）中编码聚谷氨酰胺束的CAG重复序列的扩增引起。 WT和突变ATXN1都与14-3-3蛋白相互作用，并且14-3-3过表达稳定了细胞中ATXN1的水平并增加了果蝇的ATXN1毒性。为了确定降低14-3-3水平是否可以减轻SCA1发病机理，我们将Sca7〜154Q / +小鼠饲养到缺少一个14-3-3ε等位基因的小鼠。 14-3-3ε单倍体功能不全可以挽救小脑病理和运动表型，但令人惊讶的是，它没有减轻体重，呼吸功能障碍或过早致死。生化研究表明，降低14-3-3ε水平在两个大脑区域尤其是SCA1中易受伤害的区域发挥了不同的作用：尽管小脑中的WT和突变型ATXN1水平均降低，但14-3-3ε单倍体功能不足并未改变脑干中的ATXN1水平。 。此外，14-3-3ε单倍体不足减少了将扩展的ATXN1掺入小脑而不是脑干的大毒性复合物中，并且两个区域之间ATXN1的小型和大型天然复合物的分布差异显着。这些数据表明，不同的致病机制在不同的脆弱大脑区域起作用，从而使SCA1发病机理增加了另一层次的复杂性。

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    Paymaan Jafar-Nejad; Christopher S. Ward; Ronald Richman; Harry T.Orr; Huda Y. Zoghbi;

  • 作者单位

    Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030;

    Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030;

    Departments of Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030;

    Department of Laboratory Medicine and Pathology, Department of Biochemistry, and Institute of Human Genetics, University of Minnesota, Minneapolis, MN 55455;

    Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030,Departments of Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030,Departments of Neuroscience, Baylor College of Medicine, Houston, TX 77030,The Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030-3498;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    ywhae; purkinje; capicua; rbm17; ataxin1-like;

    机译：ywhae;purkinje;capicua;rbm17;ataxin1样;

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