RNA gain-of-function in spinocerebellar ataxia type 8.
RNA gain-of-function in spinocerebellar ataxia type 8.
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DOI：
10.1371/journal.pgen.1000600
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发表时间：
2009-08
期刊：
影响因子：
4.5
通讯作者：
Ranum LP
中科院分区：
文献类型：
--
作者：
Daughters RS;Tuttle DL;Gao W;Ikeda Y;Moseley ML;Ebner TJ;Swanson MS;Ranum LP
微卫星扩张会导致许多主要结构的神经系统疾病。编码区域的扩展会导致蛋白质功能获得效应，而非编码扩展会产生有毒的RNA，从而改变MBNL和CELF蛋白的RNA剪接活性。脊髓脑性共济失调8型（SCA8）CTG CAG膨胀的双向表达会产生来自ATXN8OS基因的CUG膨胀RNA（CugeXP），并且由ATXN8 Cagexp转录本编码的几乎纯的多谷氨酰胺扩张蛋白在相反方向上表现出。在这里，我们提供了三条证据，表明RNA功能获得在SCA8：1）CugeXP转录本在大脑中选定的神经元中与MBNL1共定位的核糖核包裹物积累。 2）MBNL1的损失会增加SCA8小鼠的运动缺陷； 3）SCA8 CEGEXP转录本触发剪接变化，并增加了CUGBP1-MBNL1调控的CNS靶标，GABA-A Transporter 4（GAT4/GABT4）。 SCA8小鼠中的体内光学成像研究证实，GABT4上调与颗粒细胞层内GABA能抑制的预测丧失有关。这些数据表明，CugeXP转录本失调的MBNL/CELF调节大脑中的途径，并提供了对其他CugeXP疾病的CNS效应的机械洞察力。此外，我们证明了相对较短的CugeXP转录物引起RNA功能获得效应，并且最近在哺乳动物基因组中报道的反义转录本的数量越来越多，这表明未识别的有毒RNA有助于多谷氨酰胺CAG CAG CTGISORDERS的病理生理学。
我们描述了几条证据表明，RNA功能效应在8型（SCA8）中起着重要作用，并且对理解其他三核苷酸扩张障碍的CNS效应具有更广泛的影响2和脊椎动指7型7型。Sca8突变是双向转录的，导致Cugexp的表达来自ATXN8OS和CAGEXP转录本的转录本以及重叠ATXN8基因的多谷氨酰胺蛋白。这些数据表明，SCA8发病机理涉及RNA（CugeXP）和/或蛋白质（PolyQ）水平的功能效果。我们提供了三条证据，表明CugeXP转录物在SCA8：1）CugeXP转录本在选定神经元中与MBNL1共定位的核糖核核包含物积累。 2）MBNL1的损失会增加SCA8小鼠的运动缺陷； 3）SCA8 CEGEXP转录本引发替代剪接变化，并增加CUGBP1-MBNL1调控的CNS靶标，GABA-A Transporter 4（GAT4/GABT4），这与SCA8小鼠中GABA能抑制的预测损失有关。另外，替代剪接变化和GAT4上调由CugeXP诱导，而不是Cagexp转录本。从治疗的角度来看，有望在过表达MBNL1的细胞中逆转这种变化。
Microsatellite expansions cause a number of dominantly-inherited neurological diseases. Expansions in coding-regions cause protein gain-of-function effects, while non-coding expansions produce toxic RNAs that alter RNA splicing activities of MBNL and CELF proteins. Bi-directional expression of the spinocerebellar ataxia type 8 (SCA8) CTG CAG expansion produces CUG expansion RNAs (CUGexp) from the ATXN8OS gene and a nearly pure polyglutamine expansion protein encoded by ATXN8 CAGexp transcripts expressed in the opposite direction. Here, we present three lines of evidence that RNA gain-of-function plays a significant role in SCA8: 1) CUGexp transcripts accumulate as ribonuclear inclusions that co-localize with MBNL1 in selected neurons in the brain; 2) loss of Mbnl1 enhances motor deficits in SCA8 mice; 3) SCA8 CUGexp transcripts trigger splicing changes and increased expression of the CUGBP1-MBNL1 regulated CNS target, GABA-A transporter 4 (GAT4/Gabt4). In vivo optical imaging studies in SCA8 mice confirm that Gabt4 upregulation is associated with the predicted loss of GABAergic inhibition within the granular cell layer. These data demonstrate that CUGexp transcripts dysregulate MBNL/CELF regulated pathways in the brain and provide mechanistic insight into the CNS effects of other CUGexp disorders. Moreover, our demonstration that relatively short CUGexp transcripts cause RNA gain-of-function effects and the growing number of antisense transcripts recently reported in mammalian genomes suggest unrecognized toxic RNAs contribute to the pathophysiology of polyglutamine CAG CTG disorders. We describe several lines of evidence that RNA gain-of-function effects play a significant role in spinocerebellar ataxia type 8 (SCA8) and has broader implications for understanding the CNS effects of other trinucleotide expansion disorders including myotonic dystrophy type 1, Huntington disease like-2, and spinocerebellar ataxia type 7. The SCA8 mutation is bidirectionally transcribed resulting in the expression of CUGexp transcripts from ATXN8OS and CAGexp transcripts and polyglutamine protein from the overlapping ATXN8 gene. These data suggest that SCA8 pathogenesis involves toxic gain-of-function effects at the RNA (CUGexp) and/or protein (PolyQ) levels. We present three lines of evidence that CUGexp transcripts play a significant role in SCA8: 1) CUGexp transcripts accumulate as ribonuclear inclusions that co-localize with MBNL1 in selected neurons; 2) loss of Mbnl1 enhances motor deficits in SCA8 mice; 3) SCA8 CUGexp transcripts trigger alternative splicing changes and increased expression of the CUGBP1-MBNL1 regulated CNS target, GABA-A transporter 4 (GAT4/Gabt4) which is associated with the predicted loss of GABAergic inhibition within the granular cell layer in SCA8 mice. Additionally, alternative splicing changes and GAT4 upregulation are induced by CUGexp but not CAGexp transcripts. From a therapeutic viewpoint, it is promising that this change is reversed in cells overexpressing MBNL1.
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