Pre- and postsynaptic upregulation of FasII synergistically underlies neuropathological and behavioral phenotypes in a Drosophila model of myotonic dystrophy
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.
Authors
- Nerea Moreno (ORCID: https://orcid.org/0000-0002-5578-192X)
- Brian D. McCabe (ORCID: https://orcid.org/0000-0003-1620-0501)
- Javier Poyatos‐García (ORCID: https://orcid.org/0000-0003-3117-4743)
- Ariadna Bargiela (ORCID: https://orcid.org/0000-0003-4336-2522)
- J. Cheung (ORCID: https://orcid.org/0000-0002-3976-5073)
- C. Andrew Frank (ORCID: https://orcid.org/0000-0001-9599-421X)
- Lok I Leong
- Zhefan Stephen Chen (ORCID: https://orcid.org/0000-0002-9276-0378)
- Geneviève Gourdon (ORCID: https://orcid.org/0000-0002-3319-1347)
- Yitao Wu
- Mário Gomes‐Pereira (ORCID: https://orcid.org/0000-0002-3533-0873)
- Shaohong Peng (ORCID: https://orcid.org/0000-0002-9249-4727)
- Aline Huguet-Lachon
- Alex Chun Koon (ORCID: https://orcid.org/0000-0002-4274-7052)
- Travis Thomson (ORCID: https://orcid.org/0000-0001-8994-8241)
- Vivian Budnik (ORCID: https://orcid.org/0000-0002-7030-7847)
- Paul Magneron (ORCID: https://orcid.org/0000-0003-1135-5854)
- Joyce Man See Fung
- Juan J. Vílchez (ORCID: https://orcid.org/0000-0002-0532-2872)
- Ho Yin Edwin Chan (ORCID: https://orcid.org/0000-0003-4307-474X)
- Rubén Artero (ORCID: https://orcid.org/0000-0003-1596-047X)
- Erin Beck (ORCID: https://orcid.org/0000-0001-7839-7958)
- Noah S. Armstrong (ORCID: https://orcid.org/0000-0003-4949-1480)
- Max Zinter
- Ka Yee Winnie Yeung
- Cassandra Brewer
Institutions
- University of Iowa (US)
- Inserm (FR)
- Universitat de València (ES)
- University of Massachusetts Chan Medical School (US)
- Chinese University of Hong Kong (HK)
- Instituto de Salud Carlos III (ES)
- Sorbonne Université (FR)
- Institut de Myologie (FR)
- Centro de Investigación Biomédica en Red (ES)
- Hong Kong Biotechnology Organization (CN)
- Leitat Technological Center (ES)
- INCLIVA Health Research Institute (ES)
- Instituto de Investigación Sanitaria La Fe (ES)
- Centre de Recherche en Myologie
- École Polytechnique Fédérale de Lausanne (CH)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-18
- DOI
- https://doi.org/10.1038/s41467-025-67738-w
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Agence Nationale de la Recherche
- Fondation Jérôme Lejeune
- Innovation and Technology Commission
- College of Medicine, University of Florida