Behavioral Screening Reveals a Conserved Residue in Y-Box RNA-Binding Protein Required for Associative Learning and Memory in C. elegans

Authors

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

Publication Date

10-1-2024

Journal

PLoS Genetics

DOI

10.1371/journal.pgen.1011443

PMID

39423228

PMCID

PMC11524487

PubMedCentral® Posted Date

10-18-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Caenorhabditis elegans, Animals, Caenorhabditis elegans Proteins, Memory, Humans, RNA-Binding Proteins, Behavior, Animal, Learning, DNA Copy Number Variations, Y-Box-Binding Protein 1

Abstract

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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