Reduction of ephrin-A5 aggravates disease progression in amyotrophic lateral sclerosis
Reduction of ephrin-A5 aggravates disease progression in amyotrophic lateral sclerosis
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DOI：
10.1186/s40478-019-0759-6
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发表时间：
2019-07-12
影响因子：
7.1
通讯作者：
Lemmens, Robin
中科院分区：
文献类型：
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作者：
Rue, Laura;Oeckl, Patrick;Lemmens, Robin
肌萎缩性侧索硬化症（ALS）是一种致命的神经退行性疾病，影响脑干、脊髓和运动皮层的运动神经元。ALS具有遗传和临床异质性的特点，提示存在改变疾病表型表达的遗传因素。我们之前确定了轴突引导EphA4受体，即ephrin系统的成员，作为ALS疾病修饰因子。EphA4基因抑制挽救了斑马鱼和啮齿类动物ALS模型的运动神经元表型。阻止配体与EphA4受体结合也成功改善了疾病，提示EphA4配体在ALS中的作用。一种特殊的配体，ephrin-A5，在急性神经元损伤后反应性星形胶质细胞中上调并抑制轴突再生。此外，它在运动轴突向其目标肢体肌肉的正确寻路过程中发挥作用。我们假设在ALS啮齿动物模型中，ephrin-A5信号的组成性减少将有利于疾病进展。我们发现，在对照和症状性ALS小鼠脊髓中，ephrin-A5主要在神经元中表达。令人惊讶的是，SOD1（G93A）小鼠中ephrin-A5水平的降低加速了疾病进展，降低了生存期，而不影响疾病发作、运动神经元数量或有症状小鼠的神经肌肉连接。这些发现表明，ephrin-A5作为疾病进展的调节剂，可能在疾病的晚期发挥作用。同样，我们发现脑脊液中ephrin-A5蛋白水平较低的患者的疾病进展更具侵袭性，但不改变疾病的发病。总之，我们发现在ALS小鼠模型和人类中，ephrin-A5的表达降低可以加速疾病进展。结合我们之前关于EphA4在ALS中的作用的研究结果，我们目前的数据表明，在运动神经元疾病的病理生理中，EphA4系统的不同成员有不同的贡献。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons in the brainstem, spinal cord and motor cortex. ALS is characterized by genetic and clinical heterogeneity, suggesting the existence of genetic factors that modify the phenotypic expression of the disease. We previously identified the axonal guidance EphA4 receptor, member of the Eph-ephrin system, as an ALS disease-modifying factor. EphA4 genetic inhibition rescued the motor neuron phenotype in zebrafish and a rodent model of ALS. Preventing ligands from binding to the EphA4 receptor also successfully improved disease, suggesting a role for EphA4 ligands in ALS. One particular ligand, ephrin-A5, is upregulated in reactive astrocytes after acute neuronal injury and inhibits axonal regeneration. Moreover, it plays a role during development in the correct pathfinding of motor axons towards their target limb muscles. We hypothesized that a constitutive reduction of ephrin-A5 signalling would benefit disease progression in a rodent model for ALS. We discovered that in the spinal cord of control and symptomatic ALS mice ephrin-A5 was predominantly expressed in neurons. Surprisingly, reduction of ephrin-A5 levels in SOD1(G93A) mice accelerated disease progression and reduced survival without affecting disease onset, motor neuron numbers or innervated neuromuscular junctions in symptomatic mice. These findings suggest ephrin-A5 as a modifier of disease progression that might play a role in the later stages of the disease. Similarly, we identified a more aggressive disease progression in patients with lower ephrin-A5 protein levels in the cerebrospinal fluid without modifying disease onset. In summary, we identified reduced expression of ephrin-A5 to accelerate disease progression in a mouse model of ALS as well as in humans. Combined with our previous findings on the role of EphA4 in ALS our current data suggests different contribution for various members of the Eph-ephrin system in the pathophysiology of a motor neuron disease.