Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson's disease models
Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson's disease models
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DOI：
10.1073/pnas.0700901104
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发表时间：
2007-09-04
影响因子：
11.1
通讯作者：
Isacson, Ole
中科院分区：
文献类型：
--
作者：
Inoue, Haruhisa;Lin, Ling;Isacson, Ole
神经系统特异性富含亮氨酸的重复igg蛋白LINGO-1与Nogo-66受体复合物相关，并具有典型的EGF受体（EGFR）样酪氨酸磷酸化位点。我们的研究表明，与年龄匹配的对照组和PD动物模型相比，帕金森病（PD）患者的实质黑质中LINGO-1的表达在神经毒性病变后升高。LINGO-1表达于人类和啮齿动物大脑中脑多巴胺能（DA）神经元中。因此，在体外和氧化（6-羟多巴胺）或线粒体（n -甲基-4-苯基-1,2,3,6-四氢吡啶）毒性诱导的PD实验模型中，研究了LINGO-1在DA神经元细胞损伤反应中的作用。在LINGO-1基因敲除小鼠中，与WT相比，DA神经元存活增加，行为异常减少。这种神经保护伴随着Akt磷酸化（p-Akt）的增加。通过使用LINGO-1- fc蛋白阻断LINGO-1活性，在WT小鼠中脑DA神经元中获得了类似的体内神经保护作用。体外培养的中脑DA神经元也显示出神经保护作用和增强的神经突生长。LINGO-1拮抗剂（LINGO-1- fc、显性阴性LINGO-1和抗LINGO-1抗体）通过直接抑制LINGO-1与EGFR的结合，激活EGFR/Akt信号通路，从而改善MPP+作用下DA神经元的存活。这些结果表明，抑制LINGO-1活性的药物可以保护DA神经元免受退化，并提示富含亮氨酸的重复蛋白LINGO-1及相关蛋白类在PD中脑DA神经元的病理生理反应中发挥作用。
The nervous system-specific leucine-rich repeat Ig-containing protein LINGO-1 is associated with the Nogo-66 receptor complex and is endowed with a canonical EGF receptor (EGFR)-like tyrosine phosphorylation site. Our studies indicate that LINGO-1 expression is elevated in the substantial nigra of Parkinson's disease (PD) patients compared with age-matched controls and in animal models of PD after neurotoxic lesions. LINGO-1 expression is present in midbrain dopaminergic (DA) neurons in the human and rodent brain. Therefore, the role of LINGO-1 in cell damage responses of DA neurons was examined in vitro and in experimental models of PD induced by either oxidative (6-hydroxydopamine) or mitochondrial (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) toxicity. In LINGO-1 knockout mice, DA neuron survival was increased and behavioral abnormalities were reduced compared with WT. This neuroprotection was accompanied by increased Akt phosphorylation (p-Akt). Similar neuroprotective in vivo effects on midbrain DA neurons were obtained in WT mice by blocking LINGO-1 activity using LINGO-1-Fc protein. Neuroprotection and enhanced neurite growth were also demonstrated for midbrain DA neurons in vitro. LINGO-1 antagonists (LINGO-1-Fc, dominant negative LINGO-1, and anti-LINGO-1 antibody) improved DA neuron survival in response to MPP+ in part by mechanisms that involve activation of the EGFR/Akt signaling pathway through a direct inhibition of LINGO1's binding to EGFR. These results show that inhibitory agents of LINGO-1 activity can protect DA neurons against degeneration and indicate a role for the leucine-rich repeat protein LINGO-1 and related classes of proteins in the pathophysiological responses of midbrain DA neurons in PD.