行为筛选揭示了Y-Box RNA结合蛋白中的一个保守残基,该残基是优雅鼠联想学习和记忆所必需的。

IF 4 2区 生物学 Q1 GENETICS & HEREDITY
PLoS Genetics Pub Date : 2024-10-18 eCollection Date: 2024-10-01 DOI:10.1371/journal.pgen.1011443
Ashley N Hayden, Katie L Brandel, Edward W Pietryk, Paul R Merlau, Priyadharshini Vijayakumar, Emily J Leptich, Elizabeth S Gaytan, Meredith I Williams, Connie W Ni, Hsiao-Tuan Chao, Jill A Rosenfeld, Rachel N Arey
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引用次数: 0

摘要

RNA 结合蛋白(RBPs)调节记忆所需的翻译和可塑性。RBP 功能障碍与一系列神经系统疾病有关,认知障碍是这些疾病的主要症状。然而,在人类基因组中的 2,000 个 RBPs 中,许多还没有与神经表型相关的特征。为了解决这个问题,我们利用模式生物 elegans 来评估 20 个保守的 RBPs 在记忆中的作用。我们发现了 8 个以前未表征的记忆调节因子,其中 3 个属于 elegans Y-Box(CEY)RBP 家族。其中,我们确定cey-1是与哺乳动物Y-Box(YBX)RBPs最接近的直向同源物。我们发现,CEY-1 在神经系统中既是记忆能力所必需的,也足以促进记忆。利用人类数据集,我们在有神经症状的个体中发现了 YBX1 和 YBX3 的拷贝数变异损失和单核苷酸变异。我们在两名有神经系统症状的患者中发现了一个意义不明的 YBX3 预测有害变异 p.Asn127Tyr。将该变体引入内源性cey-1基因座会导致蠕虫出现记忆障碍。我们进一步产生了两种在cey-1基因座上表达人YBX3或YBX1的人源化蠕虫系,以检验YBX在记忆中的进化保护以及p.Asn127Tyr变体的潜在功能意义。YBX1/3都能在功能上替代cey-1,将p.Asn127Tyr引入人源化YBX3基因座会导致记忆缺陷。我们的研究强调了蠕虫是揭示记忆调节因子的模型,并确定了YBX功能障碍是罕见神经疾病的潜在新来源。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Behavioral screening reveals a conserved residue in Y-Box RNA-binding protein required for associative learning and memory in C. elegans.

RNA-binding proteins (RBPs) regulate translation and plasticity which are required for memory. RBP dysfunction has been linked to a range of neurological disorders where cognitive impairments are a key symptom. However, of the 2,000 RBPs in the human genome, many are uncharacterized with regards to neurological phenotypes. To address this, we used the model organism C. elegans to assess the role of 20 conserved RBPs in memory. We identified eight previously uncharacterized memory regulators, three of which are in the C. elegans Y-Box (CEY) RBP family. Of these, we determined that cey-1 is the closest ortholog to the mammalian Y-Box (YBX) RBPs. We found that CEY-1 is both necessary in the nervous system for memory ability and sufficient to promote memory. Leveraging human datasets, we found both copy number variation losses and single nucleotide variants in YBX1 and YBX3 in individuals with neurological symptoms. We identified one predicted deleterious YBX3 variant of unknown significance, p.Asn127Tyr, in two individuals with neurological symptoms. Introducing this variant into endogenous cey-1 locus caused memory deficits in the worm. We further generated two humanized worm lines expressing human YBX3 or YBX1 at the cey-1 locus to test evolutionary conservation of YBXs in memory and the potential functional significance of the p.Asn127Tyr variant. Both YBX1/3 can functionally replace cey-1, and introduction of p.Asn127Tyr into the humanized YBX3 locus caused memory deficits. Our study highlights the worm as a model to reveal memory regulators and identifies YBX dysfunction as a potential new source of rare neurological disease.

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来源期刊
PLoS Genetics
PLoS Genetics GENETICS & HEREDITY-
自引率
2.20%
发文量
438
期刊介绍: PLOS Genetics is run by an international Editorial Board, headed by the Editors-in-Chief, Greg Barsh (HudsonAlpha Institute of Biotechnology, and Stanford University School of Medicine) and Greg Copenhaver (The University of North Carolina at Chapel Hill). Articles published in PLOS Genetics are archived in PubMed Central and cited in PubMed.
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