JBC：LINGO-1介导抑制髓鞘形成

脱髓鞘疾病（如多发性硬化）新型治疗方法的主要目标是克服髓鞘再生障碍。LINGO-1是一个跨膜信号蛋白，主要在神经元及少突胶质细胞中表达。研究表明，LINGO-1在髓鞘形成过程中是主要的负调控因子。

Nogo受体复合物能够抑制神经元的生长，而LINGO-1在Nogo受体复合物中是以完整形式存在的。到目前为止，细胞外信号通过LINGO-1介导抑制髓鞘形成的机制还不明确。

近日，来自美国维特制药公司的研究人员发现，LINGO-1通过细胞内相互作用抑制了少突胶质细胞的终末分化，而且LINGO-1有能力反过来作用于自身。与之前的研究一致，全长的LINGO-1的过表达抑制了少突胶质细胞前体细胞(OPCs)的分化。

出乎意料的是，在与来自背根神经节(DRG)的神经元联合培养时，用可溶性的重组LINGO-1胞外域处理后，OPCs被抑制而且有髓鞘的轴突段也减少。

进一步的研究表明，可溶性LINGO-1的胞外域在与表达有全长LINGO-1的CHO细胞结合后，能够反过来作用于自身。

结果表明，在少突胶质细胞前体细胞，可溶性LINGO-1能够激活RhoA。LINGO-1能够同时作为配体及受体，并通过细胞内相互作用，负调节OPC分化及髓鞘形成。而破坏这种蛋白与蛋白相互作用能够导致LINGO-1抑制作用的下调及髓鞘形成的增加。相关论文发表在4月18日的The Journal of Biological Chemistry。

doi: 10.1074/jbc.M112.366179
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LINGO-1,a transmenbrane signaling protein, inhibits oligodendrocyte differenticaion and myelination through intercellular self-interactions

Scott Jepson, Bryan Vought, Christian H. Gross, Lu Gan, Douglas Austen, J. Daniel Frantz, Jacque Zwahlen, Derek Lowe, William Markland and Raul Krauss.

Overcoming remyelination failure is a major goal of new therapies for demyelinating diseases like multiple sclerosis. LINGO-1, a key negative regulator of myelination, is a transmembrane signaling protein expressed in both neurons and oligodendrocytes.In neurons, LINGO-1 is an integral component of the Nogo receptor complex, which inhibits axonal growth via RhoA. Since the only ligand-binding subunit of this complex, the Nogo receptor, is absent in oligodendrocytes, the extracellular signals that inhibit myelination through a LINGO-1-mediated mechanism are unknown.Here we show that LINGO-1 inhibits oligodendrocyte terminal differentiation through intercellular interactions and is capable of a self-association in trans. Consistent with previous reports, overexpression of full-length LINGO-1 inhibited differentiation of oligodendrocyte precursor cells (OPCs).Unexpectedly, treatment with a soluble recombinant LINGO-1 ectodomain also had an inhibitory effect on OPCs, and decreased myelinated axonal segments in co-cultures with neurons from dorsal root ganglia (DRG).We demonstrated LINGO-1-mediated inhibition of OPCs through intercellular signaling by using a surface-bound LINGO-1 construct expressed ectopically in astrocytes. Further investigation showed that soluble LINGO-1 ectodomain can interact with itself in trans by binding to CHO cells expressing full-length LINGO-1.Finally, we observed that soluble LINGO-1 could activate RhoA in OPCs. We propose that LINGO-1 acts as both a ligand and a receptor and that the mechanism by which it negatively regulates OPC differentiation and myelination is mediated by a homophilic intercellular interaction.Disruption of this protein-protein interaction could lead to a decrease of LINGO-1 inhibition and an increase in myelination.