tRNA 衍生片段在阿尔茨海默病中的作用：对新的疾病生物标志物和神经病理学机制的启示。
tRNA-Derived Fragments in Alzheimer's Disease: Implications for New Disease Biomarkers and Neuropathological Mechanisms.
机构信息
Department of Pediatrics, The University of Texas Medical Branch, Galveston, TX, USA.
miRcore, Ann Arbor, MI, USA.
出版信息
J Alzheimers Dis. 2021;79(2):793-806. doi: 10.3233/JAD-200917.
BACKGROUND
Alzheimer's disease (AD) is the most common type of dementia caused by irreversible neurodegeneration, with the onset mechanisms elusive. tRNA-derived RNA fragments (tRFs), a recently discovered family of small non-coding RNAs (sncRNAs), have been found to associate with many human diseases, including infectious, metabolic, and neurological diseases. However, whether tRFs play a role in human AD development is not known.
OBJECTIVE
This study aimed to explore whether tRFs are involved in human AD.
METHODS
Thirty-four postmortem human hippocampus samples were used. The expression of Drosha, Dicer, and angiogenin (ANG), three ribonucleases responsible for the biogenesis of sncRNAs, was determined by qRT-PCR and western blot. The tRFs in the hippocampus was detected by qRT-PCR or northern blot. We also used qRT-PCR to quantify NOP2/Sun RNA methyltransferase 2 (NSun2) and polyadenylation factor I subunit 1 (CLP1), two tRNA modification enzymes.
RESULTS
tRFs derived from a subset of tRNAs are significantly altered in the hippocampus of AD patients. The expression change of some tRFs showed age- and disease stage-dependent. ANG is significantly enhanced in AD, suggesting its role in inducing tRFs in AD. The expression of NSun2 in AD patients younger than 65 was significantly decreased. According to a previous report supporting NSun2-mediated tRNA methylation modification making tRNA less susceptible to ANG-mediated cleavage, our results suggested that the decrease in NSun2 may make tRNAs less methylated and subsequently enhanced tRF production from ANG-mediated tRNA cleavage.
CONCLUSION
Our studies demonstrated for the first time the involvement of tRFs in human AD.
背景
阿尔茨海默病（AD）是由不可逆转的神经退行性变引起的最常见的痴呆症，其发病机制难以捉摸。tRNA 衍生的 RNA 片段（tRFs）是最近发现的一类小非编码 RNA（sncRNA），已被发现与许多人类疾病有关，包括传染病、代谢病和神经病。然而，tRFs 是否在人类 AD 发展中起作用尚不清楚。
目的
本研究旨在探讨 tRFs 是否参与人类 AD 的发生。
方法
使用 34 个人死后海马体样本。通过 qRT-PCR 和 Western blot 测定负责 sncRNA 生物发生的三种核糖核酸酶 Drosha、Dicer 和血管生成素（ANG）的表达。通过 qRT-PCR 或 northern blot 检测海马体中的 tRF。我们还使用 qRT-PCR 定量 NOP2/Sun RNA 甲基转移酶 2（NSun2）和多聚腺苷酸化因子 I 亚基 1（CLP1），这两种 tRNA 修饰酶。
结果
AD 患者海马体中一组 tRNA 衍生的 tRFs 显著改变。一些 tRF 的表达变化表现出与年龄和疾病阶段相关。ANG 在 AD 中显著增强，提示其在 AD 中诱导 tRF 的作用。65 岁以下 AD 患者的 NSun2 表达明显降低。根据先前支持 NSun2 介导的 tRNA 甲基化修饰使 tRNA 不易受到 ANG 介导的切割的报告，我们的结果表明 NSun2 的减少可能使 tRNA 甲基化程度降低，随后增强 ANG 介导的 tRNA 切割产生 tRF。
结论
我们的研究首次证明了 tRFs 参与了人类 AD。
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