# Pre- and postsynaptic upregulation of FasII synergistically underlies neuropathological and behavioral phenotypes in a Drosophila model of myotonic dystrophy

## TL;DR

This study reveals that increased FasII in both nerve and muscle cells contributes to neurological and behavioral issues in a fruit fly model of myotonic dystrophy.

## Contribution

The novel finding is that pre- and postsynaptic FasII upregulation synergistically causes synaptic and behavioral defects in myotonic dystrophy.

## Key findings

- CUG repeat expression in both pre- and postsynaptic cells causes synaptic and locomotor defects.
- FasII upregulation is induced by CUG repeats and is necessary for the observed phenotypes.
- FasII isoform modulation can either mimic or rescue the neuropathological effects.

## Abstract

Myotonic dystrophy type 1 is a multisystemic disorder that has been extensively studied for decades, yet our understanding of its neuropathological aspect remains rudimentary. Building on an established Drosophila model, we study the neuropathological features of the disease by expressing untranslated expanded CUG repeats at the Drosophila larval neuromuscular junction. In this model, we show that both pre- and postsynaptic expressions of CUG repeats participate in inducing phenotypes in synaptic boutons, arbors, transmission and larval locomotor activity. Furthermore, expression of CUG repeats in either motorneurons or body wall muscles induces upregulation of the cell adhesion molecule FasII (NCAM1 in mammals), and the knockdown of fasII is sufficient to rescue the phenotypes. Overexpression of FasII-C, a FasII isoform with no cytoplasmic domain, mimics the phenotypes of expanded CUG expression at the neuromuscular junction. In contrary, overexpression of FasII-A-PEST+ rescues the synaptic and behavioral defects. Our study provides insights into the fundamental mechanisms underlying synapse dysregulation in myotonic dystrophy type 1.

Myotonic dystrophy type 1 affects both muscle and neuronal function, but its synaptic pathology is poorly understood. Here, the authors show that upregulation of FasII (NCAM1) in both pre- and postsynaptic cells synergistically drives neuropathological and behavioral DM1 phenotypes, which can be rescued by FasII knockdown or specific isoform modulation.