Department of Medical Biology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey.
Institute of Neuroanatomy and Cell Biology, OE 4140, Hannover Medical School, Hannover 30625, Germany.
Hum Mol Genet. 2021 Feb 25;29(24):3935-3944. doi: 10.1093/hmg/ddaa275.
Spinal muscular atrophy (SMA) is a devastating childhood disease primarily affecting lower motoneurons in the spinal cord. SMA is caused by the loss of functional survival of motoneuron (SMN) protein, leading to structural and functional alterations of the cytoskeleton in motoneurons and other cells. Loss of SMN results in impairments of microtubule architecture, but the underlying mechanisms are not completely understood. In this study, we mechanistically analyzed the effects of SMN deficiency on microtubules, demonstrating a reduced stability together with a reduction in alpha tubulin detyrosination. This was caused by increased levels of microtubule-associated protein 1B and tubulin tyrosine ligase, resulting in mitochondrial mislocalization in SMA. Our findings suggest that altered tubulin post-translational modifications and microtubule-associated proteins are involved in the pathomechanisms of SMA, such as an impaired axonal transport of mitochondria.
脊髓性肌萎缩症（SMA）是一种严重的儿童疾病，主要影响脊髓中的下运动神经元。SMA 是由运动神经元（SMN）蛋白功能丧失引起的，导致运动神经元和其他细胞的细胞骨架结构和功能发生改变。SMN 的缺失会导致微管结构受损，但潜在的机制尚不完全清楚。在这项研究中，我们从机制上分析了 SMN 缺乏对微管的影响，结果表明微管稳定性降低，α微管蛋白去酪氨酸化减少。这是由于微管相关蛋白 1B 和微管酪氨酸连接酶水平升高，导致 SMA 中线粒体的定位异常。我们的研究结果表明，微管翻译后修饰和微管相关蛋白的改变参与了 SMA 的发病机制，例如线粒体的轴突运输受损。
