Axonal Transport Defects in a Mitofusin 2 Loss of Function Model of Charcot-Marie-Tooth Disease in Zebrafish.
Axonal Transport Defects in a Mitofusin 2 Loss of Function Model of Charcot-Marie-Tooth Disease in Zebrafish.
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DOI：
10.1371/journal.pone.0067276
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Grierson AJ
中科院分区：
文献类型：
--
作者：
Chapman AL;Bennett EJ;Ramesh TM;De Vos KJ;Grierson AJ
Charcot-Marie-Tooth病（CMT）代表一组神经退行性疾病，其典型特征为运动和感觉神经元的脱髓鞘（CMT 1）或远端轴突变性（CMT 2）。大多数CMT 2病例是由线粒体融合蛋白2（MFN 2）突变引起的; MFN 2是编码负责线粒体外膜融合的蛋白质的必需基因。MFN 2突变的作用机制仍然没有完全解决。为了研究Mfn 2功能丧失在疾病中的作用，我们研究了斑马鱼Mfn 2中ENU诱导的无义突变，并在整个生物体、病理学和亚细胞水平上表征了这些鱼的表型。我们发现，与小鼠不同，斑马鱼MFN 2功能的丧失导致成年发病，进行性表型，主要症状是运动功能障碍，与CMT 2相似。突变斑马鱼表现出与神经肌肉接头改变相关的游泳进行性丧失。在细胞水平上，我们提供了直接的证据，线粒体运输沿着轴突在Mfn 2突变斑马鱼受到干扰，这表明这是一个关键的疾病机制CMT。进行性表型和病理学表明，斑马鱼将有助于进一步研究疾病的发病机制和潜在的治疗轴突形式的CMT。我们的研究结果支持这样的观点，即MFN 2突变状态应在早发复发性遗传性轴突型CMT患者中进行研究。
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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影响因子：
9.2
作者：
De Vos, KJ;Allan, VJ;Sheetz, MP
通讯作者：
Sheetz, MP
影响因子：
15.1
作者：
Sakowski SA;Lunn JS;Busta AS;Oh SS;Zamora-Berridi G;Palmer M;Rosenberg AA;Philip SG;Dowling JJ;Feldman EL
通讯作者：
Feldman EL
影响因子：
4.3
作者：
Ramesh, Tennore;Lyon, Alison N.;Beattie, Christine E.
通讯作者：
Beattie, Christine E.
影响因子：
5.3
作者：
Li, Q;Lau, A;Stanley, EF
通讯作者：
Stanley, EF
DOI：
10.1083/jcb.200211046
发表时间：
2003-01-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chen H;Detmer SA;Ewald AJ;Griffin EE;Fraser SE;Chan DC
通讯作者：
Chan DC