Rademacher Sebastian, Verheijen Bert M, Hensel Niko, Peters Miriam, Bora Gamze, Brandes Gudrun, Vieira de Sá Renata, Heidrich Natascha, Fischer Silke, Brinkmann Hella, van der Pol W Ludo, Wirth Brunhilde, Pasterkamp R Jeroen, Claus Peter
Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany.
Center for Systems Neuroscience (ZSN), Hannover, Germany.
Hum Mol Genet. 2017 Oct 15;26(20):3946-3959. doi: 10.1093/hmg/ddx282.
Cytoskeletal rearrangement during axon growth is mediated by guidance receptors and their ligands which act either as repellent, attractant or both. Regulation of the actin cytoskeleton is disturbed in Spinal Muscular Atrophy (SMA), a devastating neurodegenerative disease affecting mainly motoneurons, but receptor-ligand interactions leading to the dysregulation causing SMA are poorly understood. In this study, we analysed the role of the guidance receptor PlexinD1 in SMA pathogenesis. We showed that PlexinD1 is cleaved by metalloproteases in SMA and that this cleavage switches its function from an attractant to repellent. Moreover, we found that the PlexinD1 cleavage product binds to actin rods, pathological aggregate-like structures which had so far been described for age-related neurodegenerative diseases. Our data suggest a novel disease mechanism for SMA involving formation of actin rods as a molecular sink for a cleaved PlexinD1 fragment leading to dysregulation of receptor signaling.
轴突生长过程中的细胞骨架重排由导向受体及其配体介导，这些配体可作为排斥剂、吸引剂或兼具两者功能。脊髓性肌萎缩症（SMA）是一种主要影响运动神经元的毁灭性神经退行性疾病，其中肌动蛋白细胞骨架的调节受到干扰，但导致SMA失调的受体-配体相互作用却知之甚少。在本研究中，我们分析了导向受体PlexinD1在SMA发病机制中的作用。我们发现PlexinD1在SMA中被金属蛋白酶切割，这种切割使其功能从吸引剂转变为排斥剂。此外，我们发现PlexinD1切割产物与肌动蛋白棒结合，肌动蛋白棒是迄今为止在与年龄相关的神经退行性疾病中描述过的病理性聚集体样结构。我们的数据提示了一种SMA的新型疾病机制，涉及形成肌动蛋白棒作为切割后的PlexinD1片段的分子汇，导致受体信号失调。
