Upregulation of FasII underlies synergistic neuropathological and behavioral defects in aDrosophilamodel of myotonic dystrophy

Abstract

AbstractMyotonic dystrophy type 1 (DM1) is a multisystemic disorder that has been extensively studied for decades, yet our understanding of its neuropathological aspect remains rudimentary. In this study, we characterized a novel model of DM1 neuropathology by expressing untranslated expandedCUGrepeats at theDrosophilalarval neuromuscular junction. In this model, both pre- and postsynaptic expression ofCUGrepeats participate to induce reduction of synaptic boutons, increase of arbor disassembly and impairment of larval locomotor activity. We found that the expression ofCUGrepeats caused an upregulation of the cell adhesion molecule, FasII (NCAM1 in mammals), in both the motor neurons and the body wall muscles. Knockdown offasIIwas sufficient to rescue bouton numbers and locomotor impairment in this model. Further analyses identified the upregulation of the FasII-C isoform as a major contributor of these phenotypes. Remarkably, overexpressing the FasII-A-PEST+ isoform rescued the synaptic and behavioral defects, likely by outcompeting the upregulated FasII-C. Our study provided the foundation for a basic mechanism of synapse dysregulation in DM1.