Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
PLoS One. 2013;8(2):e54511. doi: 10.1371/journal.pone.0054511. Epub 2013 Feb 7.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. We previously showed that the expression of dynactin 1, an axon motor protein regulating retrograde transport, is markedly reduced in spinal motor neurons of sporadic ALS patients, although the mechanisms by which decreased dynactin 1 levels cause neurodegeneration have yet to be elucidated. The accumulation of autophagosomes in degenerated motor neurons is another key pathological feature of sporadic ALS. Since autophagosomes are cargo of dynein/dynactin complexes and play a crucial role in the turnover of several organelles and proteins, we hypothesized that the quantitative loss of dynactin 1 disrupts the transport of autophagosomes and induces the degeneration of motor neuron. In the present study, we generated a Caenorhabditis elegans model in which the expression of DNC-1, the homolog of dynactin 1, is specifically knocked down in motor neurons. This model exhibited severe motor defects together with axonal and neuronal degeneration. We also observed impaired movement and increased number of autophagosomes in the degenerated neurons. Furthermore, the combination of rapamycin, an activator of autophagy, and trichostatin which facilitates axonal transport dramatically ameliorated the motor phenotype and axonal degeneration of this model. Thus, our results suggest that decreased expression of dynactin 1 induces motor neuron degeneration and that the transport of autophagosomes is a novel and substantial therapeutic target for motor neuron degeneration.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是运动神经元的进行性丧失。我们之前曾表明，动力蛋白激活蛋白 1（dynactin 1）的表达在散发性 ALS 患者的脊髓运动神经元中明显降低，尽管尚未阐明 dynactin 1 水平降低导致神经退行性变的机制。自噬体在退化的运动神经元中的积累是散发性 ALS 的另一个关键病理特征。由于自噬体是动力蛋白/dynactin 复合物的货物，并且在几个细胞器和蛋白质的周转中起着至关重要的作用，因此我们假设 dynactin 1 的定量损失会破坏自噬体的运输并诱导运动神经元变性。在本研究中，我们生成了一种秀丽隐杆线虫模型，其中 DNC-1（dynactin 1 的同源物）的表达在运动神经元中特异性敲低。该模型表现出严重的运动缺陷以及轴突和神经元变性。我们还观察到变性神经元中运动障碍和自噬体数量增加。此外，雷帕霉素（一种自噬激活剂）和曲古抑菌素（一种促进轴突运输的化合物）的组合可显著改善该模型的运动表型和轴突变性。因此，我们的研究结果表明 dynactin 1 的表达降低会导致运动神经元变性，并且自噬体的运输是运动神经元变性的一个新的和重要的治疗靶点。
