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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Dysregulation of CalDAG-GEFI and CalDAG-GEFII predicts the severity of motor side-effects induced by anti-parkinsonian therapy
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Dysregulation of CalDAG-GEFI and CalDAG-GEFII predicts the severity of motor side-effects induced by anti-parkinsonian therapy

机译：CalDAG-GEFI和CalDAG-GEFII的失调可预测抗帕金森病疗法引起的运动副作用的严重程度

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摘要

Voluntary movement difficulties in Parkinson's disease are initially relieved by l-DOPA therapy, but with disease progression, the repeated L-DOPA treatments can produce debilitating motor abnormalities known as L-DOPA-induced dyskinesias. We show here that 2 striatum-enriched regulators of the Ras/Rap/ERK MAP kinase signal transduction cascade, matrix-enriched CalDAG-GEFI and striosome-enriched CalDAG-GEFII (also known as RasGRP), are strongly and inversely dysregulated in proportion to the severity of abnormal movements induced by l-DOPA in a rat model of parkinsonism. In the dopamine-depleted striatum, the l-DOPA treatments produce down-regulation of CalDAG-GEFI and up-regulation of CalDAG-GEFII mRNAs and proteins, and quantification of the Mrna levels shows that these changes are closely correlated with the severity of the dyskinesias. As these CalDAG-GEFs control ERK cascades, which are implicated in L-DOPA-induced dyskinesias, and have differential compartmental expression patterns in the striatum, we suggest that they may be key molecules involved in the expression of the dyskinesias. They thus represent promising new therapeutic targets for limiting the motor complications induced by l-DOPA therapy.
机译：l-DOPA治疗最初可缓解帕金森氏病的自愿运动困难，但随着疾病的进展，反复进行L-DOPA治疗可产生使人衰弱的运动异常，称为L-DOPA诱发的运动障碍。我们在这里显示，Ras / Rap / ERK MAP激酶信号转导级联的2个纹状体富集调节剂，基质富集的CalDAG-GEFI和核糖体富集的CalDAG-GEFII（也称为RasGRP），与比例成正比地强烈和反调l-DOPA在帕金森病大鼠模型中引起的异常运动的严重性。在多巴胺缺乏的纹状体中，l-DOPA处理可导致CalDAG-GEFI的下调和CalDAG-GEFII mRNA和蛋白的上调，Mrna水平的定量显示这些变化与肝硬化的严重程度密切相关。运动障碍。由于这些CalDAG-GEF控制ERK级联反应，这与L-DOPA诱导的运动障碍有关，并且在纹状体中具有不同的区室表达模式，因此我们建议它们可能是参与运动障碍表达的关键分子。因此，它们代表了有希望的新治疗靶标，用于限制1-DOPA治疗引起的运动并发症。

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    Jill R. Crittenden; Ippolita Cantuti-Castelvetri; Esen Saka; Christine E. Keller-McGandy; Ledia F. Hernandez; Lauren R. Kett; Anne B. Young; David G. Standaert; Ann M. Graybiel;

  • 作者单位

    Department of Brain and Cognitive Sciences and the McGovem Institute for Brain Research, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, MA 02139;

    MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Neurology Department, Charlestown, MA 02129;

    Department of Neurology, Faculty of Medicine, Hacettepe University, 06100 Ankara, Turkey;

    Department of Brain and Cognitive Sciences and the McGovem Institute for Brain Research, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, MA 02139;

    Department of Brain and Cognitive Sciences and the McGovem Institute for Brain Research, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, MA 02139;

    MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Neurology Department, Charlestown, MA 02129;

    MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Neurology Department, Charlestown, MA 02129;

    Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL 35294;

    Department of Brain and Cognitive Sciences and the McGovem Institute for Brain Research, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, MA 02139;

  • 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
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  • 关键词

    dyskinesia; ERK; l-DOPA; Parkinson's disease; striatum;

    机译：运动障碍ERK;左旋多巴;帕金森氏病;纹状体;

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