Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans.
Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans.
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DOI：
10.1371/journal.pbio.1001288
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发表时间：
2012
期刊：
影响因子：
9.8
通讯作者：
Bellen HJ
中科院分区：
文献类型：
--
作者：
Bayat V;Thiffault I;Jaiswal M;Tétreault M;Donti T;Sasarman F;Bernard G;Demers-Lamarche J;Dicaire MJ;Mathieu J;Vanasse M;Bouchard JP;Rioux MF;Lourenco CM;Li Z;Haueter C;Shoubridge EA;Graham BH;Brais B;Bellen HJ
果蝇神经退行性突变体的研究结合遗传和生化分析，导致在60名患有新型共济失调/白质脑病的患者中鉴定出多种复杂突变。已经发现越来越多的线粒体生物发生、动力学或功能所需的基因在代谢紊乱和神经系统疾病如Leigh综合征中发生突变。在一个向前的遗传筛选，以确定所需的基因的神经元功能和生存的果蝇感光神经元，我们已经确定了突变的线粒体甲硫氨酰-tRNA合成酶，Aats-met，同源的人类MARS 2。果蝇突变体表现出光感受器的年龄依赖性退化、寿命缩短和上皮组织中细胞增殖减少。我们进一步观察到，这些突变体显示氧化磷酸化缺陷，活性氧（ROS）增加，线粒体未折叠蛋白反应上调。在这些知识的帮助下，我们确定MARS 2在常染色体隐性痉挛性共济失调伴白质脑病（ARSAL）患者中发生突变。我们在所有ARSAL患者中发现了MARS 2基因的复杂重排。对患者细胞的分析显示MARS 2蛋白水平降低，线粒体蛋白合成速率降低。患者细胞还表现出复合物I活性降低、活性氧增加和细胞增殖速率减慢，与果蝇Aats-met突变体相似。神经退行性疾病，作为一个群体，是相对常见的，往往是毁灭性的，那些谁遭受他们。在果蝇、蠕虫和小鼠等模式生物中发现的人类致病基因的同源物的研究中，出现了关键的见解。在这项研究中，我们使用果蝇来鉴定新的神经变性引起的突变，并确定了Aats-met基因，其蛋白质产物参与线粒体翻译。我们发现该基因的突变会导致神经退行性变、线粒体活性受损和氧化应激升高。我们能够用抗氧化剂如维生素E来减轻这些缺陷。我们还确定，在同源的人类基因，MARS 2，不寻常的重复负责一种新型的进行性共济失调在一些法裔加拿大家庭中发现。从这些患者身上提取的细胞具有许多在果蝇中观察到的特征性缺陷，这表明果蝇突变体可用于进一步探索疾病机制和测试潜在的治疗方法。
The study of Drosophila neurodegenerative mutants combined with genetic and biochemical analyses lead to the identification of multiple complex mutations in 60 patients with a novel form of ataxia/leukoencephalopathy. An increasing number of genes required for mitochondrial biogenesis, dynamics, or function have been found to be mutated in metabolic disorders and neurological diseases such as Leigh Syndrome. In a forward genetic screen to identify genes required for neuronal function and survival in Drosophila photoreceptor neurons, we have identified mutations in the mitochondrial methionyl-tRNA synthetase, Aats-met, the homologue of human MARS2. The fly mutants exhibit age-dependent degeneration of photoreceptors, shortened lifespan, and reduced cell proliferation in epithelial tissues. We further observed that these mutants display defects in oxidative phosphorylation, increased Reactive Oxygen Species (ROS), and an upregulated mitochondrial Unfolded Protein Response. With the aid of this knowledge, we identified MARS2 to be mutated in Autosomal Recessive Spastic Ataxia with Leukoencephalopathy (ARSAL) patients. We uncovered complex rearrangements in the MARS2 gene in all ARSAL patients. Analysis of patient cells revealed decreased levels of MARS2 protein and a reduced rate of mitochondrial protein synthesis. Patient cells also exhibited reduced Complex I activity, increased ROS, and a slower cell proliferation rate, similar to Drosophila Aats-met mutants. Neurodegenerative diseases, as a group, are relatively common and often devastating to those who suffer from them. Key insights are emerging from the study of homologues of identified human disease-causing genes in model organisms such as fruit flies, worms, and mice. In this study, we used the fruit fly to identify novel neurodegeneration-causing mutations and identified the Aats-met gene, whose protein product is involved in mitochondrial translation. We found that mutations in this gene cause neurodegeneration, impaired mitochondrial activity, and elevated oxidative stress. We were able to attenuate these defects with antioxidants like Vitamin E. We also determined that unusual duplications in the homologous human gene, MARS2, were responsible for a novel type of progressive ataxia found in some French Canadian families. Cells taken from these patients have many of the characteristic defects observed in flies, showing that the fly mutants can be used to further explore disease mechanisms and test potential treatments.
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影响因子：
30.8
作者：
Bourdon, Alice;Minai, Limor;Rotig, Agnes
通讯作者：
Rotig, Agnes
影响因子：
9.8
作者：
Edvardson, Simon;Shaag, Avraham;Elpeleg, Orly
通讯作者：
Elpeleg, Orly
影响因子：
11.8
作者：
Haynes, Cole M.;Petrova, Kseniya;Ron, David
通讯作者：
Ron, David
影响因子：
64.8
作者：
CHAMBERLAIN, S;SHAW, J;WILLIAMSON, R
通讯作者：
WILLIAMSON, R
DOI：
10.1016/j.bbagen.2007.11.009
发表时间：
2008-02-01
影响因子：
3
作者：
Amer, Johnny;Atlas, Daphne;Fibach, Eitan
通讯作者：
Fibach, Eitan