Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons.
Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons.
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DOI：
10.1093/hmg/ddy127
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发表时间：
2018-06-15
影响因子：
3.5
通讯作者：
Horvath R
中科院分区：
文献类型：
--
作者：
Boczonadi V;Meyer K;Gonczarowska-Jorge H;Griffin H;Roos A;Bartsakoulia M;Bansagi B;Ricci G;Palinkas F;Zahedi RP;Bruni F;Kaspar B;Lochmüller H;Boycott KM;Müller JS;Horvath R
核编码的glyyl - trna合成酶基因（GARS）在细胞质和线粒体的蛋白质翻译中都是必不可少的。相反，不同的基因编码大多数其他tRNA合成酶的线粒体和细胞质形式。显性GARS突变被描述为遗传性神经病变，而隐性突变导致严重的儿童期发病疾病，影响骨骼肌和心脏。解释组织特异性表型-基因型关系的下游事件仍不清楚。我们在人类细胞系和GarsC210R小鼠模型中研究了GARS的线粒体功能。携带显性和隐性GARS突变的人诱导神经祖细胞（iNPCs）显示线粒体蛋白的改变，这在具有显性神经病变突变的iNPCs中更为突出。虽然iNPCs的比较蛋白质组学分析显示，隐性和显性突变中线粒体呼吸链复合体亚基、组装基因、克雷布斯循环酶和运输蛋白都发生了显著变化，但参与脂肪酸氧化的蛋白仅在隐性突变引起线粒体心肌病时发生改变。相比之下，在显性GARS突变中检测到囊泡相关膜蛋白相关蛋白B （VAPB）及其下游途径（如线粒体钙摄取和自噬）的显著改变。在GarsC210R小鼠中，类似的结果也支持了VAPB的作用。我们的数据表明，线粒体相关内质网（ER）膜（MAM）的改变可能是导致这种情况下神经病变的重要疾病机制。
The nuclear-encoded glycyl-tRNA synthetase gene (GARS) is essential for protein translation in both cytoplasm and mitochondria. In contrast, different genes encode the mitochondrial and cytosolic forms of most other tRNA synthetases. Dominant GARS mutations were described in inherited neuropathies, while recessive mutations cause severe childhood-onset disorders affecting skeletal muscle and heart. The downstream events explaining tissue-specific phenotype–genotype relations remained unclear. We investigated the mitochondrial function of GARS in human cell lines and in the GarsC210R mouse model. Human-induced neuronal progenitor cells (iNPCs) carrying dominant and recessive GARS mutations showed alterations of mitochondrial proteins, which were more prominent in iNPCs with dominant, neuropathy-causing mutations. Although comparative proteomic analysis of iNPCs showed significant changes in mitochondrial respiratory chain complex subunits, assembly genes, Krebs cycle enzymes and transport proteins in both recessive and dominant mutations, proteins involved in fatty acid oxidation were only altered by recessive mutations causing mitochondrial cardiomyopathy. In contrast, significant alterations of the vesicle-associated membrane protein-associated protein B (VAPB) and its downstream pathways such as mitochondrial calcium uptake and autophagy were detected in dominant GARS mutations. The role of VAPB has been supported by similar results in the GarsC210R mice. Our data suggest that altered mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) may be important disease mechanisms leading to neuropathy in this condition.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1016/j.cub.2016.12.038
发表时间：
2017-02-06
期刊：
Current biology : CB
影响因子：
--
作者：
Gomez-Suaga P;Paillusson S;Stoica R;Noble W;Hanger DP;Miller CCJ
通讯作者：
Miller CCJ
影响因子：
64.8
作者：
He W;Bai G;Zhou H;Wei N;White NM;Lauer J;Liu H;Shi Y;Dumitru CD;Lettieri K;Shubayev V;Jordanova A;Guergueltcheva V;Griffin PR;Burgess RW;Pfaff SL;Yang XL
通讯作者：
Yang XL
影响因子：
14.8
作者：
Guo, Min;Schimmel, Paul
通讯作者：
Schimmel, Paul
DOI：
10.1016/j.biocel.2013.12.011
发表时间：
2014-03-01
影响因子：
4
作者：
Boczonadi, Veronika;Horvath, Rita
通讯作者：
Horvath, Rita