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

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 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.

Invited review: Unearthing the mechanisms of age-related neurodegenerative disease using Caenorhabditis elegans.

As human life expectancy increases, neurodegenerative diseases present a growing public health threat, for which there are currently few effective treatments. There is an urgent need to understand the molecular and genetic underpinnings of these disorders so new therapeutic targets can be identified. Here we present the argument that the simple nematode worm Caenorhabditis elegans is a powerful tool to rapidly study neurodegenerative disorders due to their short lifespan and vast array of genetic tools, which can be combined with characterization of conserved neuronal processes and behavior orthologous to those disrupted in human disease. We review how pre-existing C. elegans models provide insight into human neurological disease as well as an overview of current tools available to study neurodegenerative diseases in the worm, with an emphasis on genetics and behavior. We also discuss open questions that C. elegans may be particularly well suited for in future studies and how worms will be a valuable preclinical model to better understand these devastating neurological disorders.