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Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS

机译：Ataxin-2中等长度的聚谷氨酰胺扩增与ALS风险增加相关

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摘要

The causes of amyotrophic lateral sclerosis (ALS), a devastating human neurodegenerative disease, are poorly understood,rnalthough the protein TDP-43 has been suggested to have a critical role in disease pathogenesis. Here we show that ataxin 2 (ATXN2), a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2, is a potent modifier of TDP-43 toxicity in animal and cellular models. ATXN2 and TDP-43 associate in a complex that depends on RNA. In spinal cord neurons of ALS patients, ATXN2 is abnormally localized; likewise, TDP-43 shows mislocalization in spinocerebellar ataxia type 2. To assess the involvement of ATXN2 in ALS, we analysed the length of the polyQ repeat in the ATXN2 gene in 915 ALS patients. We found that intermediate-length polyQ expansions (27-33 glutamines) in ATXN2 were significantly associated with ALS. These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43-ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.
机译：肌萎缩性侧索硬化症（ALS）是一种毁灭性的人类神经退行性疾病，其病因尚不清楚，尽管该蛋白TDP-43在疾病发病机理中具有关键作用。在这里，我们显示了在动物和细胞模型中TAX-43毒性的有效调节剂，紫杉醇2（ATXN2），一种在小脑共济失调2型中突变的聚谷氨酰胺（polyQ）蛋白。 ATXN2和TDP-43在依赖RNA的复合物中缔合。在ALS患者的脊髓神经元中，ATXN2异常定位。同样，TDP-43在2型脊髓小脑共济失调中显示错误定位。为评估ATXN2在ALS中的参与，我们分析了915例ALS患者ATXN2基因中polyQ重复序列的长度。我们发现ATXN2中的中等长度polyQ扩增（27-33个谷氨酰胺）与ALS显着相关。这些数据将ATXN2确定为一种相对常见的ALS易感基因。此外，这些发现表明，TDP-43-ATXN2相互作用可能是对ALS和其他TDP-43蛋白病的治疗性干预的有希望的目标。

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  • 来源
    《Nature》 |2010年第7310期|P.1069-1075iii|共8页
  • 作者

    Andrew C. Elden; Hyung-Jun Kim; Michael P. Hart; Alice S. Chen-Plotkin; Brian S. Johnson; Xiaodong Fang; Maria Armakola; Felix Geser; Robert Greene; Min Min Lu; Arun Padmanabhan; Dana Clay-Falcone; Leo McCluskey; Lauren Elman; Denise Juhr; Peter J. Gruber; Udo Rueb; Georg Auburger; John Q. Trojanowski; Virginia M.-Y. Lee; Vivianna M. Van Deerlin; Nancy M. Bonini; Aaron D. Gitler;

  • 作者单位

    Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnDepartment of Biology, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnDepartment of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnDepartment of Pathology and Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnDepartment of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnDepartment of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnDepartment of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnDepartment of Pathology and Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnDepartment of Pathology and Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnDepartment of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnDepartment of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnDepartment of Pathology and Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnDepartment of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnDepartment of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnThe Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;

    rnThe Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;

    rnInstitute of Clinical Neuroanatomy, Dr Senckenberg Anatomy, Goethe University, Frankfurt am Main D-60590, Germany;

    rnMolecular Neurogenetics, Department of Neurology, Goethe University, Frankfurt am Main D-60528, Germany;

    rnDepartment of Pathology and Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnDepartment of Pathology and Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnDepartment of Pathology and Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnDepartment of Biology, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    rnDepartment of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, 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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