ATXN2-AS, a gene antisense to ATXN2, is associated with spinocerebellar ataxia type 2 and amyotrophic lateral sclerosis.
ATXN2-AS, a gene antisense to ATXN2, is associated with spinocerebellar ataxia type 2 and amyotrophic lateral sclerosis.
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DOI：
10.1002/ana.24761
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发表时间：
2016-10
影响因子：
11.2
通讯作者：
Rudnicki DD
中科院分区：
文献类型：
--
作者：
Li PP;Sun X;Xia G;Arbez N;Paul S;Zhu S;Peng HB;Ross CA;Koeppen AH;Margolis RL;Pulst SM;Ashizawa T;Rudnicki DD
脊髓小脑性共济失调2型（SCA 2）是由共济失调蛋白2（ATXN 2）基因CAG重复扩增引起的神经退行性疾病。ATXN 2中长CAG扩增被确定为肌萎缩侧索硬化症（ALS）的危险因素。ATXN 2 CAG重复序列被翻译成多聚谷氨酰胺，SCA 2的发病机制被认为是来自于含有扩展的多聚谷氨酰胺束的ATXN 2蛋白。然而，最近的证据表明，在多个CAG/CTG疾病基因座的双向转录，使我们测试是否有其他机制的发病机制可能有助于SCA 2。在这项工作中，使用人类死后组织，各种细胞模型和动物模型，我们提供的第一个证据表明，在SCA 2基因座的反义转录有助于SCA 2的发病机制。我们证明了一个转录本的表达，含有重复作为一个CUG道，来自一个基因（ATXN 2-AS）直接反义ATXN 2。具有正常和扩增的CUG重复序列的ATXN 2-AS转录物在人死后SCA 2脑、人SCA 2成纤维细胞、诱导的SCA 2多能干细胞、SCA 2神经干细胞和含有扩增的与ALS相关的ATXN 2等位基因的类淋巴母细胞系中表达。具有CUG重复扩增的ATXN 2-AS转录物在SCA 2细胞模型中具有毒性，并在SCA 2小脑浦肯野细胞中形成RNA灶。最后，我们在SCA 2脑中检测到淀粉样β前体蛋白和N-甲基-D-天冬氨酸受体1的错误剪接，这与其他以RNA介导的发病机制为特征的疾病的发现一致。这些结果表明ATXN 2-AS在SCA 2和可能的ALS发病机制中具有作用，因此可能为这些疾病提供新的治疗靶点。
Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by a CAG repeat expansion in the gene ataxin-2 (ATXN2). ATXN2 intermediate-length CAG expansions were identified as a risk factor for amyotrophic lateral sclerosis (ALS). The ATXN2 CAG repeat is translated into polyglutamine, and SCA2 pathogenesis has been thought to derive from ATXN2 protein containing an expanded polyglutamine tract. However, recent evidence of bidirectional transcription at multiple CAG/CTG disease loci has led us to test whether additional mechanisms of pathogenesis may contribute to SCA2. In this work, using human postmortem tissue, various cell models, and animal models, we provide the first evidence that an antisense transcript at the SCA2 locus contributes to SCA2 pathogenesis. We demonstrate the expression of a transcript, containing the repeat as a CUG tract, derived from a gene (ATXN2-AS) directly antisense to ATXN2. ATXN2-AS transcripts with normal and expanded CUG repeats are expressed in human postmortem SCA2 brains, human SCA2 fibroblasts, induced SCA2 pluripotent stem cells, SCA2 neural stem cells, and lymphoblastoid lines containing an expanded ATXN2 allele associated with ALS. ATXN2-AS transcripts with a CUG repeat expansion are toxic in an SCA2 cell model and form RNA foci in SCA2 cerebellar Purkinje cells. Finally, we detected missplicing of amyloid beta precursor protein and N-methyl-D-aspartate receptor 1 in SCA2 brains, consistent with findings in other diseases characterized by RNA-mediated pathogenesis. These results suggest that ATXN2-AS has a role in SCA2 and possibly ALS pathogenesis, and may therefore provide a novel therapeutic target for these diseases.
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影响因子：
4.5
作者：
Daughters RS;Tuttle DL;Gao W;Ikeda Y;Moseley ML;Ebner TJ;Swanson MS;Ranum LP
通讯作者：
Ranum LP
影响因子：
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作者：
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影响因子：
10.6
作者：
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通讯作者：
Pletnikov, Mikhail V.
影响因子：
4.5
作者：
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Auburger, Georg