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PLoS ONE:斑马鱼模型或为开发新型遗传性疾病的疗法提供希望

来源:生物谷 2013-11-01 00:14

2013年11月1日 讯 /生物谷BIOON/ --近日,来自谢菲尔德大学等处的研究者通过研究斑马鱼模型,提出了一种治疗常见遗传性疾病的新型疗法,相关研究成果刊登于国际杂志PLoS ONE上。

腓骨肌萎缩征(CMT)是一种最常见的遗传性障碍,其主要影响个体神经系统的功能,在英国超过2万人受到该疾病的影响,该疾病通常引发患者脚进行性无力以及长期的疼痛,最终导致患者行走困难,目前并无有效的治疗手段。

研究者Grierson表示,文章中我们对遗传缺陷的斑马鱼进行研究,这种斑马鱼可以正常发育,但是其一旦到成年期后就会慢慢变得游泳困难。通过对斑马鱼肌肉的观察,研究者发现问题的关键在于运动神经元和肌肉之间连接出现了问题。

CMT代表了一类神经变性疾病,其主要特点为发生脱髓鞘作用(CMT1)或者是发生运动或者感受神经元的远端轴突退化现象(CMT2)。此前研究者使用哺乳动物模型比如小鼠来进行相关的研究工作,因为线粒体融合蛋白基因对于胚胎发育非常关键;但是本文中研究者使用了斑马鱼作为研究模型,可以使得研究更为深入透彻。

运动神经元是机体中最大的细胞,而且其高度依赖与细胞运输系统来通过长神经细胞来运输分子;研究者目前正在研究试图利用新型斑马鱼模型来开发新型针对CMT的疗法,由于斑马鱼的尺寸及其独特的生物学特性,未来斑马鱼或许还会被用于开发新型治疗人类各种疾病的药物。(生物谷Bioon.com)

Axonal Transport Defects in a Mitofusin 2 Loss of Function Model of Charcot-Marie-Tooth Disease in Zebrafish

Chapman AL, Bennett EJ, Ramesh TM, De Vos KJ, Grierson AJ

Charcot-Marie-Tooth disease (CMT) represents a group of neurodegenerative disorders typically characterised by demyelination (CMT1) or distal axon degeneration (CMT2) of motor and sensory neurons. The majority of CMT2 cases are caused by mutations in mitofusin 2 (MFN2); an essential gene encoding a protein responsible for fusion of the mitochondrial outer membrane. The mechanism of action of MFN2 mutations is still not fully resolved. To investigate a role for loss of Mfn2 function in disease we investigated an ENU-induced nonsense mutation in zebrafish MFN2 and characterised the phenotype of these fish at the whole organism, pathological, and subcellular level. We show that unlike mice, loss of MFN2 function in zebrafish leads to an adult onset, progressive phenotype with predominant symptoms of motor dysfunction similar to CMT2. Mutant zebrafish show progressive loss of swimming associated with alterations at the neuro-muscular junction. At the cellular level, we provide direct evidence that mitochondrial transport along axons is perturbed in Mfn2 mutant zebrafish, suggesting that this is a key mechanism of disease in CMT. The progressive phenotype and pathology suggest that zebrafish will be useful for further investigating the disease mechanism and potential treatment of axonal forms of CMT. Our findings support the idea that MFN2 mutation status should be investigated in patients presenting with early-onset recessively inherited axonal CMT.

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