Mutations in dynein link motor neuron degeneration to defects in retrograde transport
Mutations in dynein link motor neuron degeneration to defects in retrograde transport
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DOI：
10.1126/science.1083129
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发表时间：
2003-05-02
期刊：
影响因子：
56.9
通讯作者：
Fisher, EMC
中科院分区：
文献类型：
--
作者：
Hafezparast, M;Klocke, R;Fisher, EMC
运动神经元的退行性疾病包括一系列进行性致死性疾病，例如肌萎缩性侧索硬化症（ALS）、脊髓延髓肌萎缩症（SBMA）和脊髓性肌萎缩症（SMA）。尽管某些病例的致病基因改变是已知的，但许多SMA和SBMA样综合征以及大多数ALS病例的分子基础尚不清楚。在这里，我们表明，在细胞质动力蛋白重链的错义点突变导致进行性运动神经元变性的杂合子小鼠，并在纯合子这是伴随着路易样包涵体的形成，从而类似于人类病理学的关键特征。这些突变专门干扰动力蛋白的神经元特异性功能。
Degenerative disorders of motor neurons include a range of progressive fatal diseases such as amyotrophic lateral sclerosis (ALS), spinal-bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). Although the causative genetic alterations are known for some cases, the molecular basis of many SMA and SBMA-like syndromes and most ALS cases is unknown. Here we show that missense point mutations in the cytoplasmic dynein heavy chain result in progressive motor neuron degeneration in heterozygous mice, and in homozygotes this is accompanied by the formation of Lewy-like inclusion bodies, thus resembling key features of human pathology. These mutations exclusively perturb neuron-specific functions of dynein.