Behavioral screening of conserved RNA-binding proteins reveals CEY-1/YBX RNA-binding protein dysfunction leads to impairments in memory and cognition.

Autor:	Hayden AN; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030.; Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, 77030., Brandel KL; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030.; Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, 77030., Merlau PR; Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, 77030., Vijayakumar P; Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, 77030., Leptich EJ; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030.; Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, 77030., Pietryk EW; Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, 77030.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030., Gaytan ES; Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, 77030.; Postbaccalaureate Research Education Program, Baylor College of Medicine, Houston, TX, 77030., Ni CW; Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, 77030.; Department of Neuroscience, Rice University, Houston, TX 77005., Chao HT; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030.; Department of Pediatrics, Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, 77030.; Cain Pediatric Neurology Research Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, 77030.; McNair Medical Institute, The Robert and Janice McNair Foundation, Houston, TX, 77030., Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030.; Baylor Genetics Laboratories, Houston, TX 77021., Arey RN; Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, 77030.; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 May 02. Date of Electronic Publication: 2024 May 02.
DOI:	10.1101/2024.01.05.574402
Abstrakt:	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. e legans 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 increase 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.
Databáze:	MEDLINE
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