Hafezparast Majid, Klocke Rainer, Ruhrberg Christiana, Marquardt Andreas, Ahmad-Annuar Azlina, Bowen Samantha, Lalli Giovanna, Witherden Abi S, Hummerich Holger, Nicholson Sharon, Morgan P Jeffrey, Oozageer Ravi, Priestley John V, Averill Sharon, King Von R, Ball Simon, Peters Jo, Toda Takashi, Yamamoto Ayumu, Hiraoka Yasushi, Augustin Martin, Korthaus Dirk, Wattler Sigrid, Wabnitz Philipp, Dickneite Carmen, Lampel Stefan, Boehme Florian, Peraus Gisela, Popp Andreas, Rudelius Martina, Schlegel Juergen, Fuchs Helmut, Hrabe de Angelis Martin, Schiavo Giampietro, Shima David T, Russ Andreas P, Stumm Gabriele, Martin Joanne E, Fisher Elizabeth M C
Department of Neurodegenerative Disease, Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
Science. 2003 May 2;300(5620):808-12. doi: 10.1126/science.1083129.
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.
运动神经元的退行性疾病包括一系列进行性致命疾病，如肌萎缩侧索硬化症（ALS）、脊髓延髓肌肉萎缩症（SBMA）和脊髓性肌萎缩症（SMA）。虽然某些病例的致病基因改变已为人所知，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。在此我们表明，细胞质动力蛋白重链中的错义点突变会导致杂合小鼠出现进行性运动神经元变性，而在纯合子中，这伴随着路易体样包涵体的形成，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。
