Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany.
Center for Systems Neuroscience (ZSN), 30559 Hannover, Germany.
Cells. 2020 Nov 3;9(11):2405. doi: 10.3390/cells9112405.
Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by decreased levels of the survival of motoneuron (SMN) protein. Post-translational mechanisms for regulation of its stability are still elusive. Thus, we aimed to identify regulatory phosphorylation sites that modulate function and stability. Our results show that SMN residues S290 and S292 are phosphorylated, of which SMN pS290 has a detrimental effect on protein stability and nuclear localization. Furthermore, we propose that phosphatase and tensin homolog (PTEN), a novel phosphatase for SMN, counteracts this effect. In light of recent advancements in SMA therapies, a significant need for additional approaches has become apparent. Our study demonstrates S290 as a novel molecular target site to increase the stability of SMN. Characterization of relevant kinases and phosphatases provides not only a new understanding of SMN function, but also constitutes a novel strategy for combinatorial therapeutic approaches to increase the level of SMN in SMA.
脊髓性肌萎缩症（SMA）是一种由运动神经元存活（SMN）蛋白水平降低引起的神经肌肉疾病。其稳定性的翻译后调节机制仍难以捉摸。因此，我们旨在确定调节功能和稳定性的调节磷酸化位点。我们的结果表明，SMN 残基 S290 和 S292 被磷酸化，其中 SMN pS290 对蛋白质稳定性和核定位有不利影响。此外，我们提出磷酸酶和张力蛋白同源物（PTEN），一种新的 SMN 磷酸酶，可抵消这种作用。鉴于 SMA 治疗的最新进展，明显需要更多的方法。我们的研究表明 S290 是增加 SMN 稳定性的新的分子靶位点。相关激酶和磷酸酶的特性不仅提供了对 SMN 功能的新认识，而且构成了增加 SMA 中 SMN 水平的组合治疗方法的新策略。
