Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains.
Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains.
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定义可逆转具有朊病毒样结构域的 RNA 结合蛋白的有害相变的 RNA 寡核苷酸。
DOI：
10.1101/2023.09.04.555754
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
C
中科院分区：
文献类型：
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作者：
Guo,Lin;Mann,JacobR;Mauna,JocelynC;Copley,KatieE;Wang,Hejia;Rubien,JackD;Odeh,HanaM;Lin,JiaBei;Lee,BoLim;Ganser,Laura;Robinson,Emma;Kim,KevinM;Murthy,AnastasiaC;Paul,Tapas;Portz,Bede;Gleixner,AmandaM;Diaz,Zamia;C
带有朊病毒样结构域的rna结合蛋白，如FUS和TDP-43，浓缩成功能性液体，可转化为病理原纤维，支持致命的神经退行性疾病，包括肌萎缩侧索硬化症(ALS)/额颞叶痴呆（FTD）。在这里，我们定义了短rna（24-48个核苷酸），它们通过促进液相来阻止FUS的成纤维，以及不同的短rna，它们可以阻止FUS的凝结和成纤维，并显著地逆转FUS的凝结和成纤维。这些活性需要与FUS的多个RNA结合域相互作用，并由RNA序列、长度和结构编码。重要的是，我们定义了一种短RNA，可以溶解异常的细胞质FUS凝聚物，恢复核FUS，并减轻光遗传模型和人类运动神经元中的FUS蛋白质毒性。另一种短RNA溶解异常胞质TDP-43凝聚物，恢复核TDP-43，并减轻TDP-43的蛋白质毒性。由于短rna可以有效地传递到人脑，这些寡核苷酸可能对ALS/FTD和相关疾病具有治疗作用。
RNA-binding proteins with prion-like domains, such as FUS and TDP-43, condense into functional liquids, which can transform into pathological fibrils that underpin fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Here, we define short RNAs (24-48 nucleotides) that prevent FUS fibrillization by promoting liquid phases, and distinct short RNAs that prevent and, remarkably, reverse FUS condensation and fibrillization. These activities require interactions with multiple RNA-binding domains of FUS and are encoded by RNA sequence, length, and structure. Importantly, we define a short RNA that dissolves aberrant cytoplasmic FUS condensates, restores nuclear FUS, and mitigates FUS proteotoxicity in optogenetic models and human motor neurons. Another short RNA dissolves aberrant cytoplasmic TDP-43 condensates, restores nuclear TDP-43, and mitigates TDP-43 proteotoxicity. Since short RNAs can be effectively delivered to the human brain, these oligonucleotides could have therapeutic utility for ALS/FTD and related disorders.