Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS
Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS
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DOI：
10.1038/srep25960
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发表时间：
2016-05-16
影响因子：
4.6
通讯作者：
Hedlund, Eva
中科院分区：
文献类型：
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作者：
Allodi, Ilary;Comley, Laura;Hedlund, Eva
肌萎缩侧索硬化症(ALS)是一种致命的疾病，其特征是躯体运动神经元的丧失，导致肌肉萎缩和瘫痪。然而，控制眼球运动的动眼神经核中的运动神经元却由于未知的原因而幸免于难。我们发现，胰岛素样生长因子-2(IGF-2)在ALS的动眼神经元中持续存在，从而在该病的动眼抵抗中发挥作用。我们还发现，IGF-1受体(IGF-1R)在动眼神经元和眼外肌终板上高表达，IGF-1R是IGF结合后的生存途径。在保护ALS患者运动神经元的同时，加入IGF-2可诱导Akt磷酸化、糖原合成酶激酶-3β磷酸化和β-catenin水平。IGF-2还使脊髓性肌萎缩症(SMA)患者的运动神经元免于退化。最后，将AAV9：：IGF-2注射到SOD1(G93A)ALS小鼠的肌肉中，使小鼠的寿命延长了10%，同时保存了运动神经元并诱导了运动轴突再生。因此，我们的研究表明，动眼神经特异性表达可以用来识别保护脆弱运动神经元免受退化的候选基因。
The fatal disease amyotrophic lateral sclerosis (ALS) is characterized by the loss of somatic motor neurons leading to muscle wasting and paralysis. However, motor neurons in the oculomotor nucleus, controlling eye movement, are for unknown reasons spared. We found that insulin-like growth factor 2 ( IGF-2) was maintained in oculomotor neurons in ALS and thus could play a role in oculomotor resistance in this disease. We also showed that IGF-1 receptor ( IGF-1R), which mediates survival pathways upon IGF binding, was highly expressed in oculomotor neurons and on extraocular muscle endplate. The addition of IGF-2 induced Akt phosphorylation, glycogen synthase kinase-3 beta phosphorylation and beta-catenin levels while protecting ALS patient motor neurons. IGF-2 also rescued motor neurons derived from spinal muscular atrophy (SMA) patients from degeneration. Finally, AAV9:: IGF-2 delivery to muscles of SOD1(G93A) ALS mice extended life-span by 10%, while preserving motor neurons and inducing motor axon regeneration. Thus, our studies demonstrate that oculomotor-specific expression can be utilized to identify candidates that protect vulnerable motor neurons from degeneration.