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

Ashley N Hayden, Katie L Brandel, Paul R Merlau, Priyadharshini Vijayakumar, Emily J Leptich, Edward W Pietryk, Elizabeth S Gaytan, Connie W Ni, Hsiao-Tuan Chao, Jill A Rosenfeld, Rachel N Arey

Posted on: 15 February 2024

Preprint posted on 6 January 2024

Forgetful worms shed light on human neurological disorders

Selected by Chee Kiang Ewe

Introduction

With a fully mapped connectome composed of only 302 neurons and the ability to perform complex behaviors, C. elegans has been an exceedingly powerful model system for neurobiology [1,2]. C. elegans can form associative behavior – associating food with a particular odor (e.g., butanone) in starved worms. Typically, this associative memory lasts for 2 hours. In an egl-30 mutant background, however, the associative memory may last for more than 24 hours [3].

In this study, the authors attempted to identify novel RNA-binding proteins (RBPs) that affect memory formation and maintenance [3]. RBPs play a major role in gene regulation. In particular, RBPs may direct the localization of mRNA and facilitate local translation in neurons in response to environmental stimuli. Proper RNA regulation is important for neuroplasticity, learning and memory; mutations in RBPs have been associated with many neurological disorders [4].

Using C. elegans as a springboard, the authors identified the conserved RBP CEY-1 (C. elegans Y-Box-1) as an important regulator of associative memory. Importantly, mutations in its human orthologs Y-box binding proteins YBX1 and YBX3 are associated with neurological dysfunctions. Hence, this preprint beautifully demonstrates the strength of using C. elegans to identify conserved regulators of neuronal functions with great clinical importance [3].

Major findings

  • Genetic screen identified CEY RBPs as memory regulators

In this study, the authors performed a targeted RNAi screen and measured the worms’ ability to form short- (30 minutes post-training), intermediate- (1 hour post-training) and long-term memory (24 hours post training). Of the 20 RBPs tested, 16 appeared to affect at least one type of memory, highlighting the importance of RBPs in memory. Interestingly, three of the four members of the CEY protein family (CEY-1, -2, -3) are found to regulate different types of memory. Importantly, the mammalian ortholog (YBX) proteins are broadly expressed in the nervous system, including the memory-regulating regions, raising the possibility of conserved functions for CEY/YBX proteins in the brain.

  • CEY-1/YBX function cell-autonomously to promote memory

The authors decided to focus on CEY-1 as it is most closely related to human YBX. The authors could show that CEY-1 is broadly expressed in the nervous system, including the known memory-associated neurons. Knocking down cey-1 specifically in the nervous system of C. elegans caused deficits in short and intermediate term memory. Furthermore, overexpressing cey-1 in the nervous prolonged memory, supporting the role of CEY-1 as a memory enhancer.

  • Mutations in YBX in humans are associated with neurological dysfunction

Next, the authors examined human genomic data and found that copy number variation (CNV) in YBX1 or YBX3 is associated with neurological disorders. Most strikingly, 80% of patients with CNV deletion in YBX3 exhibit intellectual disability, while none of the genes surrounding the YBX3 locus are known to cause neurological symptoms.

  • Deleterious variant of human YBX3 causes memory defects in elegans

By examining exome and genome sequencing data from anonymized patients, the authors identified a rare deleterious allele (379A>T) in YBX3, resulting in a p.Asn127Tyr amino acid change in the cold shock domain. The p.Asn127 amino acid is highly conserved and can also be found in C. elegans. The authors introduced the mutation they found in patients into the corresponding residue in C. elegans CEY-1. They found that worms carrying the mutation showed decreased intermediate-term memory. Hence, YBX appears to play a conserved role in regulating neuronal functions and memory.

Why I chose this preprint:

This preprint reports, among other things, a novel role of CEY RBPs in memory. The authors cleverly leveraged the powerful genetic tools available for C. elegans to dissect the roles of CEY RBPs in human brains. The authors identify mutations in the human CEY orthologs (= YBX) that are associated with neurological disorders, beautifully demonstrating the translatability of C. elegans research. Identifying neuronal transcripts regulated by CEY-1/YBX will likely lead to a better understanding of how RBPs regulate neuronal plasticity which has important clinical implications.

Questions for authors

  • Have you checked the expression pattern of CEY-1 in conditioned/trained worms?
  • What are the further directions of this research project?

References

  1. Hobert O. Behavioral plasticity in C. elegans: Paradigms, circuits, genes. Journal of Neurobiology. 2003;54: 203–223. doi:10.1002/neu.10168
  2. Cook SJ, Jarrell TA, Brittin CA, Wang Y, Bloniarz AE, Yakovlev MA, et al. Whole-animal connectomes of both Caenorhabditis elegans sexes. Nature. 2019;571: 63–71. doi:10.1038/s41586-019-1352-7
  3. Hayden AN, Brandel KL, Merlau PR, Vijayakumar P, Leptich EJ, Pietryk EW, et al. Behavioral screening of conserved RNA-binding proteins reveals CEY-1/YBX RNA-binding protein dysfunction leads to impairments in memory and cognition. bioRxiv. 2024; 2024.01.05.574402. doi:10.1101/2024.01.05.574402
  4. Prashad S, Gopal PP. RNA-binding proteins in neurological development and disease. RNA Biol. 18: 972–987. doi:10.1080/15476286.2020.1809186

 

Tags: memory, neurodegeneration, rna regulation, worm

doi: https://doi.org/10.1242/prelights.36532

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Author's response

Rachel N Arey shared

  • Have you checked the expression pattern of CEY-1 in conditioned/trained worms?

Have you been sitting in on our lab meetings? This is a question that we are very interested in pursuing and just starting to answer. Previous work in mammals, such as in Ostroff et al., 2019, have reported an increase in the translation of mRNAs encoding for RNA binding molecules after a training paradigm, so we would like to know if something similar is happening with CEY-1. Thankfully, we have all the tools at our disposal to hopefully answer your question soon!

  • What are the further directions of this research project?

This is the exciting part about discovering something new – you have the opportunity to pursue so many different directions. We have shown that you need CEY-1 for memory ability, but we want to know why is it important? We are interested in how CEY-1 is regulated in the context of memory training, which takes us back to the previous question, and if it is under the control of specific plasticity regulating pathways. Also, CEY-1 is an RNA binding protein and therefore regulates the translation of mRNAs. We want to know what its targets are, which are important for the ability to learn and remember, and if there is something specific about how it regulates its targets in the context of conditioning/training. Lastly, we are incredibly excited about the discovery of a potentially deleterious variant in YBX3 in human populations. We would love to examine more human genetics datasets to find other potential variants of interest in both YBX3 and YBX1, not only from a more clinical perspective, but to also use them as a tool to study the biology of these proteins further. These are just a few avenues that we are interested in, but there are many more.

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