转运RNA的表观遗传修饰及其异常对神经退行性变性疾病的影响  

Abnormal transfer RNA epigenetic modifications and related impact on neurodegenerative diseases

作　　者：唐明敏 毕洪运 董子敬 曾玲晖 TANG Mingmin;BI Hongyun;DONG Zijing;ZENG Linghui(School of Medicine,Hangzhou City University,Hangzhou 310015,China;Department of Neurology,the Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310009,China;Liangzhu Laboratory,Zhejiang University,Hangzhou 311121,China;School of Brain Science and Brain Medicine,Zhejiang University School of Medicine,Hangzhou 310058,China)

机构地区：[1]浙大城市学院医学院,浙江杭州310015 [2]浙江大学医学院附属第二医院神经内科,浙江杭州310009 [3]浙江大学良渚实验室,浙江杭州311121 [4]浙江大学医学院脑科学与脑医学学院,浙江杭州310058

出　　处：《浙江大学学报(医学版)》2025年第1期58-69,共12页Journal of Zhejiang University(Medical Sciences)

基　　金：国家自然科学基金(82304472);浙大城市学院科研培育基金(X-202103,J-202105)。

摘　　要：神经退行性变性疾病是一组以中枢或周围神经系统神经元的功能和结构完整性逐渐丧失为特征的神经系统疾病。这类疾病的病因复杂,致病机制及药物靶点的研究仍面临诸多难题。转运RNA(tRNA)修饰在调节密码子识别、维持分子结构稳定性以及影响tRNA衍生片段(tRF)产生等方面发挥着关键作用,对神经发育和神经系统的生理功能具有重要作用。异常的tRNA修饰与多种神经退行性变性疾病的发病机制密切相关,特别是延伸因子复合物依赖的tRNA修饰和甲基化修饰异常能导致翻译过程和tRF水平变化,进而干扰蛋白质稳态和细胞应激反应,影响神经元存活。此外,神经退行性变性疾病患者体内tRF水平也显示出显著变化,特定tRF对神经退行性变性疾病有着不同的影响。本文从tRNA表观遗传修饰的生物学功能出发,深入探讨其异常在神经退行性变性疾病中的作用,包括经典的密码子识别功能和非经典的tRF生成机制,最后讨论了tRNA修饰可以作为治疗神经退行性变性疾病的潜在靶点。Neurodegenerative diseases are a heterogeneous group of neurological disorders characterized by progressive loss of neurons in the central or peripheral nervous system.Research on the pathogenesis and drug targets of these diseases still faces many challenges due to the complex etiology.In recent years,the role of epigenetic modifications in transfer RNA(tRNA)in neurodegenerative diseases has attracted widespread attention.The tRNA modifications are crucial for regulating codon recognition,maintaining molecular structural stability,and the generation of tRNA-derived fragments(tRFs).Recent studies have highlighted a close association between abnormal tRNA modifications and the pathogenesis of various neurodegenerative diseases,especially for abnormalities of elongator complex-dependent tRNA modification and methylation modification,which impact the translation process and tRFs levels.These changes regulate protein homeostasis and cellular stress responses,ultimately influencing the survival of neuronal cells.Moreover,significant changes in tRFs levels have been observed in neurodegenerative diseases,and specific tRFs show distinct effects on neurodegenerative diseases.This review aims to provide an overview of the physiological functions of tRNA epigenetic modifications and their regulatory mechanisms in neurodegenerative diseases,covering both classical functions such as codon recognition and non-classical functions such as tRFs biogenesis.Additionally,the potential of targeting tRNA modifications for therapeutic applications is discussed.

关 键 词：神经退行性变性疾病 转运RNA 表观遗传修饰 转运RNA衍生片段 综述 

分 类 号：R394[医药卫生—医学遗传学] R741.02[医药卫生—基础医学]