Therapeutic reduction of GGGGCC repeat RNA levels by hnRNPA3 suppresses neurodegeneration in Drosophila models of C9orf72-linked ALS/FTD
Therapeutic reduction of GGGGCC repeat RNA levels by hnRNPA3 suppresses neurodegeneration in Drosophila models of C9orf72-linked ALS/FTD
复制标题
hnRNPA3 治疗性降低 GGGGCC 重复 RNA 水平可抑制 C9orf72 相关 ALS/FTD 果蝇模型中的神经变性
DOI：
10.1093/hmg/ddac298
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发表时间：
2023
影响因子：
3.5
通讯作者：
Nagai Yoshitaka
中科院分区：
文献类型：
--
作者：
Taminato Tomoya;Takeuchi Toshihide;Ueyama Morio;Mori Kohji;Ikeda Manabu;Mochizuki Hideki;Nagai Yoshitaka
C9orf72基因内GGGGCC六核苷酸重复序列的异常扩展是肌萎缩侧索硬化症(ALS)和额颞部痴呆(FTD)最常见的遗传原因。C9orf72连锁ALS/FTD(C9-ALS/FTD)的主要病理特征是含有GGGGCC重复序列的RNA的聚集，以及这些重复RNA通过非常规翻译产生的二肽重复蛋白(DPR)的沉积，两者都被认为在这些疾病的发病机制中起着至关重要的作用。由于GGGGCC重复RNA可能是C9-ALS/FTD致病级联中最上游的治疗靶点，降低GGGGCC重复RNA的细胞水平有望减轻重复RNA的毒性，因此将成为治疗C9-ALS/FTD的一种疾病修饰治疗策略。在本研究中，我们使用C9-ALS/FTD的果蝇模型证明，与GGGGCC重复RNA结合的一组人RNA结合蛋白的表达上调，包括hnRNPA3、IGF2BP1、hnRNPA2B1、hnRNPR和SF3B3，降低了GGGGCC重复RNA的水平，从而抑制了神经退变。我们进一步表明，hnRNPA3介导的GGGGCC重复RNA的减少抑制了疾病的病理，如RNA病灶和DPR积聚。这些结果表明，hnRNPA3和其他RNA结合蛋白负向调节GGGGCC重复RNA的水平，减轻重复RNA在体内的毒性，表明内源性RNA结合蛋白介导的重复RNA降低途径在治疗C9-ALS/FTD方面具有潜在的治疗潜力。
The abnormal expansion of GGGGCC hexanucleotide repeats within theC9orf72gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The accumulation of GGGGCC repeat-containing RNAs as RNA foci, and the deposition of dipeptide repeat proteins (DPR) produced from these repeat RNAs by unconventional translation are major pathological hallmarks ofC9orf72-linked ALS/FTD (C9-ALS/FTD), and are both thought to play a crucial role in the pathogenesis of these diseases. Because GGGGCC repeat RNA is likely to be the most upstream therapeutic target in the pathogenic cascade of C9-ALS/FTD, lowering the cellular level of GGGGCC repeat RNA is expected to mitigate repeat RNA toxicity, and will therefore be a disease-modifying therapeutic strategy for the treatment of C9-ALS/FTD. In this study, we demonstrated using aDrosophilamodel of C9-ALS/FTD that elevated expression of a subset of human RNA-binding proteins that bind to GGGGCC repeat RNA, including hnRNPA3, IGF2BP1, hnRNPA2B1, hnRNPR and SF3B3, reduces the level of GGGGCC repeat RNA, resulting in the suppression of neurodegeneration. We further showed that hnRNPA3-mediated reduction of GGGGCC repeat RNA suppresses disease pathology, such as RNA foci and DPR accumulation. These results demonstrate that hnRNPA3 and other RNA-binding proteins negatively regulate the level of GGGGCC repeat RNA, and mitigate repeat RNA toxicityin vivo, indicating the therapeutic potential of the repeat RNA-lowering approach mediated by endogenous RNA-binding proteins for the treatment of C9-ALS/FTD.