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<p>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 <i>Drosophila</i> model, we study the neuropathological features of the disease by expressing untranslated expanded <i>CUG</i> repeats at the <i>Drosophila</i> larval neuromuscular junction. In this model, we show that both pre- and postsynaptic expressions of <i>CUG</i> repeats participate in inducing phenotypes in synaptic boutons, arbors, transmission and larval locomotor activity. Furthermore, expression of <i>CUG</i> repeats in either motorneurons or body wall muscles induces upregulation of the cell adhesion molecule FasII (NCAM1 in mammals), and the knockdown of <i>fasII</i> is sufficient to rescue the phenotypes. Overexpression of FasII-C, a FasII isoform with no cytoplasmic domain, mimics the phenotypes of expanded <i>CUG</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月18日

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  • Alex Chun Koon,
  • Ka Yee Winnie Yeung,
  • Yitao Wu,
  • Lok I Leong,
  • John Tsun Po Cheung,
  • Zhefan Stephen Chen,
  • Shaohong Isaac Peng,
  • Noah S. Armstrong,
  • C. Andrew Frank,
  • Paul Magneron,
  • Mário Gomes-Pereira,
  • Joyce Man See Fung,
  • Ariadna Bargiela,
  • Nerea Moreno,
  • Javier Poyatos-Garcia,
  • Juan Vilchez,
  • Aline Huguet-Lachon,
  • Cassandra Kussius Brewer,
  • Max Zinter,
  • Erin S. Beck,
  • Rubén Artero,
  • Genevieve Gourdon,
  • Vivian Budnik,
  • Travis Thomson,
  • Brian D. McCabe,
  • Ho Yin Edwin Chan

摘要

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.