LaMonte Bernadette H, Wallace Karen E, Holloway Beth A, Shelly Spencer S, Ascaño Jennifer, Tokito Mariko, Van Winkle Thomas, Howland David S, Holzbaur Erika L F
Department of Physiology, School of Medicine, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia 19104, USA.
Neuron. 2002 May 30;34(5):715-27. doi: 10.1016/s0896-6273(02)00696-7.
To test the hypothesis that inhibition of axonal transport is sufficient to cause motor neuron degeneration such as that observed in amyotrophic lateral sclerosis (ALS), we engineered a targeted disruption of the dynein-dynactin complex in postnatal motor neurons of transgenic mice. Dynamitin overexpression was found to disassemble dynactin, a required activator of cytoplasmic dynein, resulting in an inhibition of retrograde axonal transport. Mice overexpressing dynamitin demonstrate a late-onset progressive motor neuron degenerative disease characterized by decreased strength and endurance, motor neuron degeneration and loss, and denervation of muscle. Previous transgenic mouse models of ALS have shown abnormalities in microtubule-based axonal transport. In this report, we describe a mouse model that confirms the critical role of disrupted axonal transport in the pathogenesis of motor neuron degenerative disease.
为了验证轴突运输抑制足以导致运动神经元变性（如在肌萎缩侧索硬化症（ALS）中观察到的那样）这一假说，我们对转基因小鼠出生后的运动神经元中的动力蛋白 - 动力蛋白激活蛋白复合物进行了靶向破坏。发现过表达动力素会分解动力蛋白激活蛋白，而动力蛋白激活蛋白是胞质动力蛋白所需的激活剂，从而导致逆行轴突运输受到抑制。过表达动力素的小鼠表现出一种迟发性进行性运动神经元退行性疾病，其特征为力量和耐力下降、运动神经元变性和丧失以及肌肉去神经支配。先前的ALS转基因小鼠模型已显示基于微管的轴突运输存在异常。在本报告中，我们描述了一种小鼠模型，该模型证实了轴突运输中断在运动神经元退行性疾病发病机制中的关键作用。
