Trak1 mutation disrupts GABAA receptor homeostasis in hypertonic mice
Trak1 mutation disrupts GABAA receptor homeostasis in hypertonic mice
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DOI：
10.1038/ng1715
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发表时间：
2006-02-01
期刊：
影响因子：
30.8
通讯作者：
Lahn, BT
中科院分区：
文献类型：
--
作者：
Gilbert, SL;Zhang, L;Lahn, BT
高张力（Hypertonia）是由中枢神经系统（CNS）的运动通路缺陷导致的，在许多神经疾病中都能观察到，包括脑瘫、中风、脊髓损伤、僵人综合征、痉挛性截瘫、肌张力障碍和帕金森病。高张力（hyrt）基因突变的小鼠表现出严重的高张力作为其主要症状。在此我们表明，hyrt突变小鼠的中枢神经系统中γ - 氨基丁酸A 型（GABA(A)）受体水平比野生型小鼠低得多，尤其是在下运动神经元中，这表明突变体的高张力可能是由GABA介导的运动神经元抑制缺陷引起的。我们克隆了相关基因，即转运蛋白、驱动蛋白结合蛋白1（Trak1），并表明其蛋白产物与GABA(A)受体相互作用。我们的数据表明Trak1是GABA(A)受体稳态的关键调节因子，并强调了hyrt小鼠作为研究与人类神经疾病相关的高张力分子病因学模型的重要性。
Hypertonia, which results from motor pathway defects in the central nervous system (CNS), is observed in numerous neurological conditions, including cerebral palsy, stroke, spinal cord injury, stiff-person syndrome, spastic paraplegia, dystonia and Parkinson disease. Mice with mutation in the hypertonic (hyrt) gene exhibit severe hypertonia as their primary symptom. Here we show that hyrt mutant mice have much lower levels of gamma-aminobutyric acid type A (GABA(A)) receptors in their CNS, particularly the lower motor neurons, than do wild-type mice, indicating that the hypertonicity of the mutants is likely to be caused by deficits in GABA-mediated motor neuron inhibition. We cloned the responsible gene, trafficking protein, kinesin binding 1 (Trak1), and showed that its protein product interacts with GABAA receptors. Our data implicate Trak1 as a crucial regulator of GABA(A) receptor homeostasis and underscore the importance of hyrt mice as a model for studying the molecular etiology of hypertonia associated with human neurological diseases.