RAN Translation of the Expanded CAG Repeats in the SCA3 Disease Context
RAN Translation of the Expanded CAG Repeats in the SCA3 Disease Context
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DOI：
10.1016/j.jmb.2020.10.033
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发表时间：
2020-12-04
影响因子：
5.6
通讯作者：
Fiszer, Agnieszka
中科院分区：
文献类型：
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作者：
Jazurek-Ciesiolka, Magdalena;Ciesiolka, Adam;Fiszer, Agnieszka
脊髓小脑型共济失调3型(SCA3)是一种由ATXN3基因编码ataxin-3蛋白的CAG重复扩增引起的进行性神经退行性疾病。尽管进行了广泛的研究，但对SCA3的确切致病机制仍不清楚。在本研究中，为了深入了解扩展的CAG重复在SCA3中引起的毒性，我们在表达翻译或非规范翻译的ATXN3序列的各种细胞模型中全面研究了重复相关的非ATG(RAN)翻译，并增加了CAG重复的数量。我们证明，只有在致病长度的CAG重复序列的情况下，才能发现两种SCA3RAN蛋白，即聚谷氨酰胺(PolyQ)和聚丙氨酸(PolyA)。尽管RAN PolyQ和RAN PolyA蛋白具有不同的细胞定位，但它们经常在同一细胞中共表达，损害核的完整性并诱导细胞凋亡。我们首次提供了对SCA3RAN翻译的机械性见解，表明围绕重复区域的ATXN3序列对SCA3RAN翻译的起始和效率有影响。我们发现，多聚Q蛋白的Ran翻译始于CAG重复序列上游的非同源密码子，而Ran Polya蛋白可能在重复序列中翻译。此外，整合的应激反应激活增强了SCA3RAN的翻译。我们的发现表明，ATXN3序列在触发SCA3RAN翻译过程中起着重要作用，SCA3RAN蛋白可能导致细胞毒性。(C)2020年提交人(S)。爱思唯尔有限公司出版。
Spinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the ATXN3 gene encoding the ataxin-3 protein. Despite extensive research the exact pathogenic mechanisms of SCA3 are still not understood in depth. In the present study, to gain insight into the toxicity induced by the expanded CAG repeats in SCA3, we comprehensively investigated repeat-associated non-ATG (RAN) translation in various cellular models expressing translated or non-canonically translated ATXN3 sequences with an increasing number of CAG repeats. We demonstrate that two SCA3 RAN proteins, polyglutamine (polyQ) and polyalanine (polyA), are found only in the case of CAG repeats of pathogenic length. Despite having distinct cellular localization, RAN polyQ and RAN polyA proteins are very often coexpressed in the same cell, impairing nuclear integrity and inducing apoptosis. We provide for the first time mechanistic insights into SCA3 RAN translation indicating that ATXN3 sequences surrounding the repeat region have an impact on SCA3 RAN translation initiation and efficiency. We revealed that RAN translation of polyQ proteins starts at non-cognate codons upstream of the CAG repeats, whereas RAN polyA proteins are likely translated within repeats. Furthermore, integrated stress response activation enhances SCA3 RAN translation. Our findings suggest that the ATXN3 sequence context plays an important role in triggering SCA3 RAN translation and that SCA3 RAN proteins may cause cellular toxicity. (C) 2020 The Author(s). Published by Elsevier Ltd.