反义重复转录本的 AUG 依赖性翻译促进 C9ORF72 扩增携带者产生二肽重复蛋白
AUG-Dependent Translation of Antisense Repeat Transcripts Contributes to Dipeptide Repeat Protein Production in C9ORF72 Expansion Carriers
C9ORF72 基因中的六核苷酸重复扩增是肌萎缩侧索硬化（ALS）和额颞叶痴呆最常见的遗传病因。该重复序列双向转录产生的 RNA 会被翻译成二肽重复蛋白，但其起始机制尚不清楚。研究者用基因编辑和阻断型反义寡核苷酸（人工合成的短链核酸，可抑制特定 RNA）证明，反义重复 RNA 上游含 AUG（起始密码子）的区域是高效生成 poly(GP) 蛋白所必需的。靶向该区域的寡核苷酸可降低 poly(PR) 和 poly(GP) 水平而不影响重复 RNA 量。研究提示翻译阻断型寡核苷酸可能成为治疗策略。
为什么推荐给您：揭示 C9ORF72 二肽重复蛋白生成的新翻译机制，并提出潜在治疗靶点，转化前景明确。
不需要生物学背景，多打比方
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摘要Abstract
A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Bidirectional transcription of the repeat expansion generates sense and antisense RNAs that are translated into dipeptide repeat (DPR) proteins, but the mechanisms of translation initiation remain incompletely understood. Here, we used CRISPR-Cas9 genome editing and steric-blocking antisense oligonucleotides (ASOs) to investigate the role of AUG codons within the antisense repeat RNA. Deletion of an AUG-containing region upstream of the antisense repeats markedly reduced poly(GP) production without affecting antisense RNA levels, demonstrating that this sequence is required for efficient poly(GP) synthesis. We further found that unspliced sense transcripts containing the repeat expansion likely serve as templates for poly(GA) and poly(GR) production in motor neurons. Finally, ASOs targeting the antisense AUG-containing region reduced poly(PR) and poly(GP) levels without altering repeat RNA abundance, supporting a role for AUG-dependent translation of the antisense repeat RNA. These findings provide new insights into the mechanisms of DPR production and suggest that translation-blocking ASOs may represent a therapeutic strategy for C9ORF72-associated ALS/FTD.