Upregulation of FasII underlies synergistic neuropathological and behavioral defects in a Drosophila model of myotonic dystrophy
Koon, A. C.; Yeung, K. Y. W.; Leong, L. I.; Chen, Z. S.; Peng, S. I.; Fung, J. M. S.; Wu, Y.; Armstrong, N. S.; Bargiela, A.; Moreno, N.; Poyatos, J.; Vilchez, J.; Magneron, P.; Huguet, A.; Brewer, C. K.; Beck, E. S.; Artero, R.; Gomes-Pereira, M.; Gourdon, G.; Budnik, V.; Frank, C. A.; McCabe, B. D.; Chan, H. Y. E.
Show abstract
Myotonic 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 expanded CUG repeats at the Drosophila larval neuromuscular junction. In this model, both pre- and postsynaptic expression of CUG repeats participate to induce reduction of synaptic boutons, increase of arbor disassembly and impairment of larval locomotor activity. We found that the expression of CUG repeats caused an upregulation of the cell adhesion molecule, FasII (NCAM1 in mammals), in both the motor neurons and the body wall muscles. Knockdown of fasII was 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.
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