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

Abstract

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 organismC. elegansto 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 theC. elegansY-Box (CEY) RNA-binding protein family:cey-1, cey-2, andcey-3. We determined thatcey-1is 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 humanYBX1andYBX3may be associated with neurological symptoms including intellectual disability, which mirror our findings inC. elegans. We identified a similar association with a rare, mono-allelicYBX3variant in individuals with neurological findings. Strikingly, introducing this predicted deleteriousYBX3variant into the endogenouscey-1locus 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.