Asadian Negar, Aprico Andrea, Chen Moore, Yuen Daniel, Johnston Angus P R, Kilpatrick Trevor J, Binder Michele D
The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Glia. 2024 Aug;72(8):1392-1401. doi: 10.1002/glia.24534. Epub 2024 Apr 4.
Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) characterized by demyelination, axonal damage and, for the majority of people, a decline in neurological function in the long-term. Remyelination could assist in the protection of axons and their functional recovery, but such therapies are not, as yet, available. The TAM (Tyro3, Axl, and MERTK) receptor ligand GAS6 potentiates myelination in vitro and promotes recovery in pre-clinical models of MS. However, it has remained unclear which TAM receptor is responsible for transducing this effect and whether post-translational modification of GAS6 is required. In this study, we show that the promotion of myelination requires post-translational modification of the GLA domain of GAS6 via vitamin K-dependent γ-carboxylation. We also confirmed that the intracerebroventricular provision of GAS6 for 2 weeks to demyelinated wild-type (WT) mice challenged with cuprizone increased the density of myelinated axons in the corpus callosum by over 2-fold compared with vehicle control. Conversely, the provision of GAS6 to Tyro3 KO mice did not significantly improve the density of myelinated axons. The improvement in remyelination following the provision of GAS6 to WT mice was also accompanied by an increased density of CC1 mature oligodendrocytes compared with vehicle control, whereas this improvement was not observed in the absence of Tyro3. This effect occurs independent of any influence on microglial activation. This work therefore establishes that the remyelinative activity of GAS6 is dependent on Tyro3 and includes potentiation of oligodendrocyte numbers.
多发性硬化症是一种中枢神经系统（CNS）的自身免疫性疾病，其特征为脱髓鞘、轴突损伤，并且对大多数人来说，长期神经功能会下降。髓鞘再生有助于保护轴突及其功能恢复，但目前尚无此类疗法。TAM（Tyro3、Axl和MERTK）受体配体GAS6在体外可增强髓鞘形成，并在MS临床前模型中促进恢复。然而，尚不清楚哪种TAM受体负责转导这种效应，以及是否需要GAS6的翻译后修饰。在本研究中，我们表明髓鞘形成的促进需要通过维生素K依赖性γ羧化对GAS6的GLA结构域进行翻译后修饰。我们还证实，向用铜离子载体攻击的脱髓鞘野生型（WT）小鼠脑室内提供GAS6两周，与载体对照相比，胼胝体中有髓轴突的密度增加了2倍以上。相反，向Tyro3基因敲除小鼠提供GAS6并没有显著提高有髓轴突的密度。与载体对照相比，向WT小鼠提供GAS6后髓鞘再生的改善还伴随着CC1成熟少突胶质细胞密度的增加，而在没有Tyro3的情况下未观察到这种改善。这种效应的发生与对小胶质细胞激活的任何影响无关。因此，这项工作确定了GAS6的髓鞘再生活性依赖于Tyro3，并且包括增强少突胶质细胞数量。
