PAK1和NF2/Merlin的拮抗作用驱动少突胶质细胞髓鞘膜扩张  

Antagonistic actions of PAK1 and NF2/Merlin drive myelin membrane expansion in oligodendrocytes

作　　者：杜一星(编译) 

机构地区：[1]不详

出　　处：《神经损伤与功能重建》2024年第7期F0003-F0003,共1页Neural Injury and Functional Reconstruction

摘　　要：在中枢神经系统中,少突胶质细胞(OL)髓鞘的形成依赖于肌动蛋白细胞骨架从聚合到解聚的转变。触发这种转变的分子机制尚未阐明。本研究确定P21活化激酶1(PAK1)是OL中肌动蛋白解聚的主要调节因子。我们的结果表明,PAK1以激酶抑制形式在OL中积累,从而触发肌动蛋白分解,进而导致髓鞘膜扩张。值得注意的是,PAK1结合伙伴的蛋白质组学分析使我们能够确定NF2/Merlin是其内源性抑制剂。本研究表明,OL中的Nf2敲低会导致PAK1活化、肌动蛋白聚合和OL髓鞘膜扩张减少。通过使用PAK1抑制剂治疗可以挽救这种影响。本研究还提供了证据表明,少突胶质细胞中特定的Pak1功能丧失会刺激体内髓鞘增厚。总体而言,我们的数据表明PAK1和NF2/Merlin对OL肌动蛋白细胞骨架的拮抗作用对于髓鞘的正常形成至关重要。这些发现对研究脱髓鞘疾病和神经发育障碍的机制和治疗有着重要意义。In the central nervous system,the formation of myelin by oligodendrocytes(OLs)relies on the switch from the polymerization of the actin cytoskeleton to its depolymerization.The molecular mechanisms that trigger this switch have yet to be elucidated.Here,we identified P21-activated kinase 1(PAK1)as a major regulator of actin depolymerization in OLs.Our results demonstrate that PAK1 accumulates in OLs in a kinase-inhibited form,trigger-ing actin disassembly and,consequently,myelin membrane expansion.Remarkably,proteomic analysis of PAK1 binding partners enabled the identification of NF2/Merlin as its endogenous inhibitor.Our findings indicate that Nf2 knockdown in OLs results in PAK1 activation,actin polymerization,and a reduction in OL myelin membrane expan-sion.This effect is rescued by treatment with a PAK1 inhibitor.We also provide evidence that the specific Pak1 loss-of-function in oligodendroglia stimulates the thickening of myelin sheaths in vivo.Overall,our data indicate that the antagonistic actions of PAK1 and NF2/Merlin on the actin cytoskeleton of the OLs are critical for proper my-elin formation.These findings have broad mechanistic and therapeutic implications in demyelinating diseases and neurodevelopmental disorders.

关 键 词：NF2/Merlin P21活化激酶1 肌动蛋白细胞骨架 膜 髓鞘 少突胶质细胞 

分 类 号：R741[医药卫生—神经病学与精神病学] R741.02[医药卫生—临床医学]