mRNA转录后调控异常在阿尔茨海默病发病机制中的研究进展

基础医学与临床 ›› 2021, Vol. 41 ›› Issue (5): 749-752.

mRNA转录后调控异常在阿尔茨海默病发病机制中的研究进展

孙静瑶, 佟伟民, 牛亚梅^*

中国医学科学院基础医学研究所北京协和医学院基础学院病理学系, 北京 100005

收稿日期:2020-05-09 修回日期:2020-08-24 出版日期:2021-05-05 发布日期:2021-05-06
通讯作者: ^*niuym@ibms.pumc.edu.cn
基金资助:
中国医学科学院医学与健康科技创新工程(2016I2M1004)

Research progress on post-transcriptional dysregulation of mRNA in pathogenesis of Alzheimer's disease

SUN Jing-yao, TONG Wei-min, NIU Ya-mei^*

Department of Pathology, Institute of Basic Medical Sciences CAMS,School of Basic Medicine PUMC, Beijing 100005, China

Received:2020-05-09 Revised:2020-08-24 Online:2021-05-05 Published:2021-05-06
Contact: ^*niuym@ibms.pumc.edu.cn

摘要/Abstract

摘要： mRNA在转录合成之后,会经历剪接、出核、翻译或降解等转录后调控模式,这是确保蛋白质合成与功能发挥的重要前提,而脑内mRNA转录后调控异常是导致阿尔茨海默病(AD)发生的原因之一。本文介绍了AD发病过程中APP、MAPT等致病基因的转录后调控异常事件;同时基于表观转录修饰RNA N⁶-甲基腺嘌呤甲基化(m⁶A)对RNA代谢的调节作用、以及其上游调控因子在AD中的异常表现,提出m⁶A 介导的转录后调控异常可能是引起AD发病的重要机制之一。

关键词: 阿尔茨海默病, mRNA, 转录后调控, RNA m⁶A甲基化

Abstract: Post-transcriptional regulation of mRNA is an essential step from RNA transcription to gene translation, the process includes mRNA splicing, nuclear export, translation, and decay. Post-transcriptional dysregulation in the brain is one of the causal factors of Alzheimer's disease. This review summarizes the dysfunctional post-transcriptional regulation of APP, MAPT and many other risk genes of AD identified so far. Meanwhile, RNA N⁶-methyladenosine methylation is the most abundant epitranscriptomic mark on mRNA and regulate almost every step in mRNA metabolism. Due to the abnormal expression of m⁶A regulators and participation in alternative splicing of risk genes in AD, the hypothesis proposes that post-transcriptional dys-regulation mediated by m⁶A may function as a novel pathogenic factor of AD .

Key words: Alzheimer's disease, mRNA, post-transcriptional regulation, RNA m⁶A methylation

中图分类号:

R741.02

孙静瑶, 佟伟民, 牛亚梅. mRNA转录后调控异常在阿尔茨海默病发病机制中的研究进展[J]. 基础医学与临床, 2021, 41(5): 749-752.

SUN Jing-yao, TONG Wei-min, NIU Ya-mei. Research progress on post-transcriptional dysregulation of mRNA in pathogenesis of Alzheimer's disease[J]. Basic & Clinical Medicine, 2021, 41(5): 749-752.

参考文献

[1] Twine NA, Janitz K, Wilkins MR, et al. Whole transcriptome sequencing reveals gene expression and splicing differences in brain regions affected by Alzheimer's disease[J]. PLoS One, 2011, 6: e16266. doi:10.1371/journal.pone.0016266.
[2] Braggin JE, Bucks SA, Course MM, et al. Alternative splicing in a presenilin 2 variant associated with Alzheimer disease[J]. Ann Clin Transl Neurol, 2019, 6: 762-777.
[3] Chang JL, Hinrich AJ, Roman B, et al. Targeting amyloid-beta precursor protein, APP, splicing with antisense oligonucleotides reduces toxic amyloid-beta production[J]. Mol Ther, 2018, 26: 1539-1551.
[4] Eftekharzadeh B, Daigle JG, Kapinos LE, et al. Tau protein disrupts nucleocytoplasmic transport in Alzheimer's disease[J]. Neuron, 2018, 99: 925-940.
[5] Ma C, Chang M, Lv H, et al. RNA m⁶A methylation participates in regulation of postnatal development of the mouse cerebellum[J]. Genome Biol, 2018, 19: 68. doi:10.1186/s13059-018-1435-z.
[6] Fragkouli A, Koukouraki P, Vlachos IS, et al. Neuronal ELAVL proteins utilize AUF-1 as a co-partner to induce neuron-specific alternative splicing of APP[J]. Sci Rep, 2017, 7: 44507. doi:10.1038/srep44507.
[7] Kolisnyk B, Al-Onaizi M, Soreq L, et al. Cholinergic surveillance over hippocampal RNA metabolism and Alzheimer's-like pathology[J]. Cereb Cortex, 2017, 27: 3553-3567.
[8] Wang ZH, Liu P, Liu X, et al. Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies[J]. J Exp Med, 2018, 215: 3038-3056.
[9] Del-Aguila JL, Benitez BA, Li Z, et al. TREM2 brain transcript-specific studies in AD and TREM2 mutation carriers[J]. Mol Neurodegener, 2019, 14: 18. doi:10.1186/s13024-019-0319-3.
[10] Cornelison GL, Levy SA, Jenson T, et al. Tau-induced nuclear envelope invagination causes a toxic accumulation of mRNA in Drosophila[J]. Aging Cell, 2019, 18: e12847. doi:10.1111/acel.12847.
[11] Koren SA, Hamm MJ, Meier SE, et al. Tau drives translational selectivity by interacting with ribosomal proteins[J]. Acta Neuropathol, 2019, 137: 571-583.
[12] Maina MB, Bailey LJ, Doherty AJ, et al. The involvement of Abeta42 and tau in nucleolar and protein synthesis machinery dysfunction[J]. Front Cell Neurosci, 2018, 12: 220. doi:10.3389/fncel.2018.00220.
[13] Cefaliello C, Penna E, Barbato C, et al. Deregulated local protein synthesis in the brain synaptosomes of a mouse model for Alzheimer's disease[J]. Mol Neurobiol, 2020, 57: 1529-1541.
[14] Kobayashi S, Tanaka T, Soeda Y. Local somatodendritic translation and hyperphosphorylation of tau protein triggered by AMPA and NMDA receptor stimulation[J]. EBioMedicine, 2017, 20: 120-136.
[15] Renoux AJ, Carducci NM, Ahmady AA. Ahmady, et al. Fragile X mental retardation protein expression in Alzheimer's disease[J]. Front Genet, 2014, 5: 360. doi:10.3389/fgene.2014.00360.
[16] Zeng T, Ni H, Yu Y, et al. BACE1-AS prevents BACE1 mRNA degradation through the sequestration of BACE1-targeting miRNAs[J]. J Chem Neuroanat, 2019, 98: 87-96.
[17] J. Gu J, Wu F, Xu W, et al. TDP-43 suppresses tau expression via promoting its mRNA instability[J]. Nucleic Acids Res, 2017, 45: 6177-6193.
[18] Alkallas R, Fish L, Goodarzi H, et al. Inference of RNA decay rate from transcriptional profiling highlights the regulatory programs of Alzheimer's disease[J]. Nat Commun, 2017, 8: 909. doi:10.1038/s41467-017-00867-z.
[19] Li H, Ren Y, Mao K, et al. FTO is involved in Alzheimer's disease by targeting TSC1-mTOR-Tau signal-ing[J]. Biochem Biophys Res Commun, 2018, 498: 234-239.
[20] Xiao W, Adhikari S, Dahal U, et al. Nuclear m⁶A reader YTHDC1 regulates mRNA splicing[J]. Mol Cell, 2016, 61: 507-519.
[21] Roundtree IA, Luo GZ, Zhang Z, et al. YTHDC1 mediates nuclear export of N⁶-methyladenosine methylated mRNAs[J]. eLife, 2017, 6: e31311. doi:10.7554/eLife.31311.
[22] Zhao X, Yang Y, Sun BF, et al. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis[J]. Cell Res, 2014, 24: 1403-1419.
[23] Chang M, Lv H, Zhang W, et al. Region-specific RNA m⁶A methylation represents a new layer of control in the gene regulatory network in the mouse brain[J]. Open Biol, 2017, 7: 170166. doi:10.1098/rsob.170166.
[24] Edens BM, Vissers C, Su J, et al. FMRP modulates neural differentiation through m⁶A-dependent mRNA nuclear export[J]. Cell Rep, 2019, 28: 845-854.