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RAN Translation Regulated by Muscleblind Proteins in Myotonic Dystrophy Type 2.
Neuron ( IF 16.2 ) Pub Date : 2017-Sep-13 , DOI: 10.1016/j.neuron.2017.08.039
Tao Zu , John D. Cleary , Yuanjing Liu , Monica Bañez-Coronel , Jodi L. Bubenik , Fatma Ayhan , Tetsuo Ashizawa , Guangbin Xia , H. Brent Clark , Anthony T. Yachnis , Maurice S. Swanson , Laura P.W. Ranum

Several microsatellite-expansion diseases are characterized by the accumulation of RNA foci and RAN proteins, raising the possibility of a mechanistic connection. We explored this question using myotonic dystrophy type 2, a multisystemic disease thought to be primarily caused by RNA gain-of-function effects. We demonstrate that the DM2 CCTG⋅CAGG expansion expresses sense and antisense tetrapeptide poly-(LPAC) and poly-(QAGR) RAN proteins, respectively. In DM2 autopsy brains, LPAC is found in neurons, astrocytes, and glia in gray matter, and antisense QAGR proteins accumulate within white matter. LPAC and QAGR proteins are toxic to cells independent of RNA gain of function. RNA foci and nuclear sequestration of CCUG transcripts by MBNL1 is inversely correlated with LPAC expression. These data suggest a model that involves nuclear retention of expansion RNAs by RNA-binding proteins (RBPs) and an acute phase in which expansion RNAs exceed RBP sequestration capacity, are exported to the cytoplasm, and undergo RAN translation. VIDEO ABSTRACT.

中文翻译:

RAN翻译受2型强直性营养不良的肌盲蛋白调控。

RNA病灶和RAN蛋白的积累是几种微卫星扩张性疾病的特征,从而增加了机械性连接的可能性。我们使用2型强直性肌营养不良症探讨了这个问题,这是一种多系统疾病,主要是由RNA功能获得效应引起的。我们证明DM2CCTG⋅CAGG扩展分别表达有义和反义四肽聚(LPAC)和聚(QAGR)RAN蛋白。在DM2尸检大脑中,LPAC在灰质的神经元,星形胶质细胞和神经胶质中发现,反义QAGR蛋白在白质中积累。LPAC和QAGR蛋白对细胞具有毒性,而与RNA功能获得无关。MBNL1的CCUG转录本的RNA病灶和核隔离与LPAC表达成反比。这些数据表明了一个模型,该模型涉及通过RNA结合蛋白(RBP)保留扩展RNA的核并处于急性期,其中扩展RNA超过RBP螯合能力,输出到细胞质并进行RAN翻译。视频摘要。
更新日期:2017-09-20
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