Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), 35 Convent Drive, Bethesda, MD 20892-3705, USA.
Trends Neurosci. 2010 Feb;33(2):59-66. doi: 10.1016/j.tins.2009.11.001.
Charcot-Marie-Tooth disease type 2D, a hereditary axonal neuropathy, is caused by mutations in glycyl-tRNA synthetase (GARS). The mutations are distributed throughout the protein in multiple functional domains. In biochemical and cell culture experiments, some mutant forms of GARS have been indistinguishable from wild-type protein, suggesting that these in vitro tests might not adequately assess the aberrant activity responsible for axonal degeneration. Recently, mouse and fly models have offered new insights into the disease mechanism. There are still gaps in our understanding of how mutations in a ubiquitously expressed component of the translation machinery result in axonal neuropathy. Here, we review recent reports, weigh the evidence for and against possible mechanisms and suggest areas of focus for future work.
腓骨肌萎缩症 2D 型，一种遗传性轴索性神经病，由甘氨酰-tRNA 合成酶 (GARS) 的突变引起。这些突变分布在该蛋白的多个功能域中。在生化和细胞培养实验中，一些突变形式的 GARS 与野生型蛋白无法区分，这表明这些体外试验可能无法充分评估导致轴突退化的异常活性。最近，小鼠和果蝇模型为疾病机制提供了新的见解。对于翻译机制中普遍表达的成分的突变如何导致轴索性神经病，我们的理解仍存在空白。在这里，我们综述了最近的报告，权衡了可能的机制的证据，并提出了未来工作的重点领域。
