Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion
Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion
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DOI：
10.1093/hmg/ddn280
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发表时间：
2008-12-01
影响因子：
3.5
通讯作者：
Suomalainen, Anu
中科院分区：
文献类型：
--
作者：
Hakonen, Anna H.;Goffart, Steffi;Suomalainen, Anu
婴儿起病的脊髓小脑性共济失调(IOSCA)是一种严重的神经退行性疾病，由PEO1基因的隐性突变引起，导致其解旋酶结构域的线粒体解旋酶Twinkle发生Y508C改变。然而，在这种疾病中没有发现线粒体功能障碍。我们在这里研究了IOSCA对中枢神经系统的影响，以及IOSCA突变蛋白的体外性能。线粒体DNA分析的结果与类似的青少年或成人起病的共济失调综合征--线粒体隐性共济失调综合征(MIRAS)的结果进行了比较，线粒体隐性共济失调综合征是由线粒体DNA聚合酶(Polg)的W748S突变引起的。我们在这里显示IOSCA脑没有mtDNA缺失或mtDNA点突变的增加，而MIRAS脑显示mtDNA的多个缺失。然而，IOSCA，在较小程度上也包括MIRAS，显示大脑和肝脏中的mtDNA枯竭。在这两种疾病中，尤其是大神经元表现为呼吸链复合体I(CI)缺乏，但IOSCA中CIV也减少。但是，IOSCA突变体的解旋酶活性、六聚体和类核结构没有受到影响。缺乏体外解旋酶缺陷或细胞培养表型表明，Twinkle-Y508C功能障碍以高度上下文和细胞类型特异性的方式影响mtDNA的维持。我们的结果表明IOSCA是线粒体DNA耗竭综合征的新成员。
Infantile-onset spinocerebellar ataxia (IOSCA) is a severe neurodegenerative disorder caused by the recessive mutation in PEO1, leading to an Y508C change in the mitochondrial helicase Twinkle, in its helicase domain. However, no mitochondrial dysfunction has been found in this disease. We studied here the consequences of IOSCA for the central nervous system, as well as the in vitro performance of the IOSCA mutant protein. The results of the mtDNA analyses were compared to findings in a similar juvenile or adult-onset ataxia syndrome, mitochondrial recessive ataxia syndrome (MIRAS), caused by the W748S mutation in the mitochondrial DNA polymerase (POLG). We show here that IOSCA brain does not harbor mtDNA deletions or increased amount of mtDNA point mutations, whereas MIRAS brain shows multiple deletions of mtDNA. However, IOSCA, and to a lesser extent also MIRAS, show mtDNA depletion in the brain and the liver. In both diseases, especially large neurons show respiratory chain complex I (CI) deficiency, but also CIV is decreased in IOSCA. Helicase activity, hexamerization and nucleoid structure of the IOSCA mutant were, however, unaffected. The lack of in vitro helicase defect or cell culture phenotype suggest that Twinkle-Y508C dysfunction affects mtDNA maintenance in a highly context and cell-type specific manner. Our results indicate that IOSCA is a new member of the mitochondrial DNA depletion syndromes.