Insight Into Spinocerebellar Ataxia Type 31 (SCA31) From Drosophila Model.
Insight Into Spinocerebellar Ataxia Type 31 (SCA31) From Drosophila Model.
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DOI：
10.3389/fnins.2021.648133
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发表时间：
2021
影响因子：
4.3
通讯作者：
Ishikawa K
中科院分区：
文献类型：
--
作者：
Ishiguro T;Nagai Y;Ishikawa K
脊髓小脑性共济失调31型（SCA 31）是一种进行性神经退行性疾病，其特征在于小脑中的浦肯野细胞变性。其遗传原因是一个2.5- 3.8 kb长的复杂五核苷酸重复插入，包含（TGGAA）n，（TAGAA）n，（TAAAA）n和（TAAAATAGAA）n，位于两个不同基因共享的内含子中：脑表达与NEDD 4 -1（BEAN 1）和胸苷激酶2（TK 2）相关。在这些重复序列中，（TGGAA）n重复序列是唯一与SCA 31分离的序列，这有力地表明了其致病性。在SCA 31患者的大脑中，发现含有扩增的UGGAA重复序列（UGGAAexp）的突变BEAN 1转录物在小脑浦肯野细胞核中形成称为RNA灶的异常RNA结构。此外，在浦肯野细胞的细胞质中检测到由UGGAAexp RNA翻译的五肽重复（PPR）蛋白，poly（Trp-Asn-Gly-Met-Glu）的沉积。为了揭示SCA 31中UGGAAexp的发病机制，我们建立了表达UGGAAexp RNA的SCA 31果蝇模型。UGGAAexp的毒性取决于其长度和表达水平，这伴随着果蝇中RNA灶的积累和重复相关PPR蛋白的翻译，与SCA 31患者脑中的观察结果一致。我们还发现，TDP-43，FUS和hnRNPA 2B 1，运动神经元疾病相关的RNA结合蛋白结合UGGAAexp RNA，作为RNA伴侣调节RNA焦点的形成和重复相关的翻译。进一步研究RNA结合蛋白作为RNA分子伴侣的作用也可能为SCA 31以外的其他微卫星重复扩增疾病提供新的治疗策略。
Spinocerebellar ataxia type 31 (SCA31) is a progressive neurodegenerative disease characterized by degeneration of Purkinje cells in the cerebellum. Its genetic cause is a 2.5- to 3.8-kb-long complex pentanucleotide repeat insertion containing (TGGAA)n, (TAGAA)n, (TAAAA)n, and (TAAAATAGAA)n located in an intron shared by two different genes: brain expressed associated with NEDD4-1 (BEAN1) and thymidine kinase 2 (TK2). Among these repeat sequences, (TGGAA)n repeat was the only sequence segregating with SCA31, which strongly suggests its pathogenicity. In SCA31 patient brains, the mutant BEAN1 transcript containing expanded UGGAA repeats (UGGAAexp) was found to form abnormal RNA structures called RNA foci in cerebellar Purkinje cell nuclei. In addition, the deposition of pentapeptide repeat (PPR) proteins, poly(Trp-Asn-Gly-Met-Glu), translated from UGGAAexp RNA, was detected in the cytoplasm of Purkinje cells. To uncover the pathogenesis of UGGAAexp in SCA31, we generated Drosophila models of SCA31 expressing UGGAAexp RNA. The toxicity of UGGAAexp depended on its length and expression level, which was accompanied by the accumulation of RNA foci and translation of repeat-associated PPR proteins in Drosophila, consistent with the observation in SCA31 patient brains. We also revealed that TDP-43, FUS, and hnRNPA2B1, motor neuron disease–linked RNA-binding proteins bound to UGGAAexp RNA, act as RNA chaperones to regulate the formation of RNA foci and repeat-associated translation. Further research on the role of RNA-binding proteins as RNA chaperones may also provide a novel therapeutic strategy for other microsatellite repeat expansion diseases besides SCA31.
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.1422273112
发表时间：
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