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MIR-NAT抑制MAPT翻译并在神经退行性病变中协助蛋白稳态平衡
2021-05-21 21:54

英国伦敦大学学院Rohan de Silva、Roberto Simone等研究人员发现,MIR-NAT抑制MAPT翻译并在神经退行性病变中协助蛋白稳态平衡。相关论文于2021年5月19日在线发表在《自然》杂志上。

研究人员发现了MAPT-AS1,这是一种大脑富集的天然反义转录本(NAT),在灵长类动物中保守并且包含一个嵌入的MIR(mammalian-wide interspersed repeat) ,该序列通过与MAPT mRNA内部核糖体进入位点竞争核糖体RNA配对来抑制tau翻译。MAPT编码tau,一种稳定轴突微管的神经元内在失调蛋白(IDP)。高磷酸化、易于聚集的tau形成了tau病理的标志性内含物。MAPT突变会导致家族性额颞叶痴呆,形成MAPT H1单倍型的常见变异是许多陶氏病和帕金森氏病的重要危险因素。

值得注意的是,MAPT-AS1或来自MAPT-AS1(包括MIR)的最小必需序列的表达降低神经元的tau水平(而沉默MAPT-AS1的表达则增加),并与人脑的tau病理相关。此外,研究人员发现了许多带有嵌入MIR的NAT(MIR-NAT),它们在与神经变性和/或IDP编码相关的编码基因中过表达,并证实了MIR-NAT介导的对此类基因PLCG1的翻译控制。

这些结果证明了MAPT-AS1在tau病理中的关键作用,并揭示了MIR-NAT对IDP严格翻译控制的潜在广泛贡献,特别是与蛋白质变性在神经退行性变中相关。

据了解,人类基因组表达了成千上万的NAT,从而可以调节表观遗传状态、转录、RNA稳定性或重叠基因的翻译。

附:英文原文

Title: MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration

Author: Roberto Simone, Faiza Javad, Warren Emmett, Oscar G. Wilkins, Filipa Loureno Almeida, Natalia Barahona-Torres, Justyna Zareba-Paslawska, Mazdak Ehteramyan, Paola Zuccotti, Angelika Modelska, Kavitha Siva, Gurvir S. Virdi, Jamie S. Mitchell, Jasmine Harley, Victoria A. Kay, Geshanthi Hondhamuni, Daniah Trabzuni, Mina Ryten, Selina Wray, Elisavet Preza, Demis A. Kia, Alan Pittman, Raffaele Ferrari, Claudia Manzoni, Andrew Lees, John A. Hardy, Michela A. Denti, Alessandro Quattrone, Rickie Patani, Per Svenningsson, Thomas T. Warner, Vincent Plagnol, Jernej Ule, Rohan de Silva

Issue&Volume: 2021-05-19

Abstract: The human genome expresses thousands of natural antisense transcripts (NAT) that can regulate epigenetic state, transcription, RNA stability or translation of their overlapping genes1,2. Here we describe MAPT-AS1, a brain-enriched NAT that is conserved in primates and contains an embedded mammalian-wide interspersed repeat (MIR), which represses tau translation by competing for ribosomal RNA pairing with the MAPT mRNA internal ribosome entry site3. MAPT encodes tau, a neuronal intrinsically disordered protein (IDP) that stabilizes axonal microtubules. Hyperphosphorylated, aggregation-prone tau forms the hallmark inclusions of tauopathies4. Mutations in MAPT cause familial frontotemporal dementia, and common variations forming the MAPT H1 haplotype are a significant risk factor in many tauopathies5 and Parkinson’s disease. Notably, expression of MAPT-AS1 or minimal essential sequences from MAPT-AS1 (including MIR) reduces—whereas silencing MAPT-AS1 expression increases—neuronal tau levels, and correlate with tau pathology in human brain. Moreover, we identified many additional NATs with embedded MIRs (MIR-NATs), which are overrepresented at coding genes linked to neurodegeneration and/or encoding IDPs, and confirmed MIR-NAT-mediated translational control of one such gene, PLCG1. These results demonstrate a key role for MAPT-AS1 in tauopathies and reveal a potentially broad contribution of MIR-NATs to the tightly controlled translation of IDPs6, with particular relevance for proteostasis in neurodegeneration.

DOI: 10.1038/s41586-021-03556-6

Source: https://www.nature.com/articles/s41586-021-03556-6

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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