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) are key regulators of translation and plasticity in the nervous system, which are processes required for learning and memory. Indeed, RBP dysfunction has been linked to a wide range of neurological disorders where cognitive impairments are a key symptom. However, the human genome encodes nearly 2,000 RBPs, many of which have yet to be characterized with regards to neurological phenotypes like associative behaviors. To address this, we used the model organism C. elegans to perform a targeted screen assessing the role of 20 conserved RBPs in learning and memory. We identified 16 associative memory regulators, eight of which are novel. Intriguingly, three novel memory regulators are in the C. elegans Y-Box (CEY) RNA-binding protein family: cey-1 , cey-2 , and cey-3 . We determined that cey-1 is the closest ortholog to the mammalian Y-Box RNA-binding (YBX) proteins and that CEY-1 is specifically required in the nervous system for the ability to remember. Additionally, CEY-1 is a memory promoting molecule, as increasing CEY-1 only in the nervous system improves memory. We also examined human copy number variation datasets and found that copy number deletions in the human YBX1 and YBX3 may be associated with neurological symptoms including intellectual disability, which mirror our findings in C. elegans. We identified a similar association with a rare, mono-allelic YBX3 variant in individuals with neurological findings. Strikingly, introducing this predicted deleterious YBX3 variant into the endogenous cey-1 locus caused memory deficits in the worm. Our study highlights that high-throughput approaches in the worm reveal novel and conserved regulators of memory and identified a potential new source of rare neurological disease linked to RBP dysfunction.