RAN Translation in Huntington Disease.
RAN Translation in Huntington Disease.
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DOI：
10.1016/j.neuron.2015.10.038
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发表时间：
2015-11-18
期刊：
影响因子：
16.2
通讯作者：
Ranum LP
中科院分区：
文献类型：
--
作者：
Bañez-Coronel M;Ayhan F;Tarabochia AD;Zu T;Perez BA;Tusi SK;Pletnikova O;Borchelt DR;Ross CA;Margolis RL;Yachnis AT;Troncoso JC;Ranum LP
亨廷顿病（HD）是由亨廷顿蛋白（HTT）基因中CAG·CTG扩增引起的。虽然大多数研究都集中在HTT polyGln扩展蛋白上，但我们证明了四种额外的新型均聚扩展蛋白（polyAla，polySer，polyLeu和polyCys）在HD人脑中积累。这些有义和反义重复序列相关的非ATG（RAN）翻译蛋白在具有神经元丢失、小胶质细胞活化和凋亡的脑区域（包括尾状核/壳核、白色物质）以及在青少年发病病例中的小脑中积累最丰富。RAN蛋白的积累和聚集是长度依赖性的，并且单个RAN蛋白对神经细胞是有毒的，而不依赖于RNA效应。这些数据表明，RAN蛋白有助于HD和治疗策略，针对正义和反义基因可能需要在HD患者的疗效。这是第一次证明RAN蛋白在位于开放阅读框中的扩增中表达，并表明RAN翻译也可能导致其他多聚谷氨酰胺疾病。
Huntington disease (HD) is caused by a CAG·CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGln-expansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum. RAN protein accumulation and aggregation are length dependent, and individual RAN proteins are toxic to neural cells independent of RNA effects. These data suggest RAN proteins contribute to HD and that therapeutic strategies targeting both sense and antisense genes may be required for efficacy in HD patients. This is the first demonstration that RAN proteins are expressed across an expansion located in an open reading frame and suggests RAN translation may also contribute to other poly-glutamine diseases.