BEYOND THE NUCLEOLUS: EXPLORING ROLE OF SNORNA FUNCTION AT THE SYNAPSE

Synaptic dysfunction is a defining feature of several neurodevelopmental and neurodegenerative disorders with growing evidence linking it to disruptions in RNA homeostasis and condensate dynamics. In addition to coding RNAs, multiple classes of non-coding RNAs (ncRNAs) have been identified at the axons and synapses. These ncRNAs tightly regulate local transport and translation, supporting maintenance of synaptic plasticity. Among these ncRNAs, small nucleolar RNAs (snoRNAs) are classically considered nucleolar and primarily known for guiding ribosomal RNA modifications. However, C/D box snoRNAs (SNORD) 115 and SNORD 116 have been detected in hippocampal synaptosomes and extracellular vesicles. They are genetically linked to Prader-Willi syndrome and are biomarkers for Alzheimer’s disease, suggesting novel extranuclear role of SNORDs at the synapse. Here we identify that presynaptic condensates of synapsin-1 and α-synuclein recruit SNORDs. Our in-vitro reconstitution assays show SNORDs modulate material properties of synapsin-1 condensates supporting a model in which SNORDs play an architectural role. Together, this data suggests a new, structural role of ncRNAs in synaptic activity. Disruption of these SNORD-dependent assemblies may provide a mechanistic link between altered RNA organization, impaired synaptic function, and downstream neurodegenerative disease pathways.