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An international multidisciplinary research team led by the School of Life Sciences at The Chinese University of Hong Kong (CUHK) has uncovered a novel molecular mechanism driving the neuropathological features of myotonic dystrophy type 1 (DM1). This breakthrough finding has been published in the prestigious scientific journal Nature Communications.

DM1 is the most common adult-onset muscular dystrophy, affecting approximately one in 2,100 to 8,000 individuals worldwide – yet it remains classified as a “rare disease” due to its prevalence of below one in 2,000 in many populations. Caused by an abnormal repetition of CTG in the DMPK gene, DM1 leads to multisystemic involvement, including progressive muscle weakness, myotonia (delayed muscle relaxation), cardiac arrhythmia, respiratory complications and cognitive impairment. Clinical research conducted between 2006 and 2016 across major hospitals in Hong Kong involved 91 DM1 patients. This local cohort analysis revealed that larger CTG repeat sizes correlate with earlier disease onset and a higher burden of systemic complications, including cardiac and respiratory issues. Despite significant advances in understanding its muscle pathology over the past two decades, the neurological manifestations – such as synaptic dysfunction and neuronal loss – have remained largely unexplored, contributing to substantial morbidity and reduced quality of life.

Unravelling the hidden neurological toll of DM1 to enhance patient care and therapy development

Building on this clinical foundation, the team led by CUHK’s Professor Edwin Chan Ho-yin developed a streamlined animal model to probe DM1’s neuropathology. Fruit flies (Drosophila melanogaster) serve as excellent models for the study of DM1 due to their conserved essential genes, similar muscle deterioration to humans, and the well-developed genetic tools available to investigate disease mechanisms. This elegant system recapitulates key disease features, allowing precise interrogation of synaptic dynamics. Using the Drosophila DM1 model of the disease, Professor Chan’s team identified specific criteria for synaptic loss, pinpointing FasII upregulation as the central culprit. FasII is the fruit fly counterpart of the human cell adhesion molecule NCAM1. Dysregulated NCAM1 expression was subsequently confirmed in a mouse DM1 model and postmortem brain tissues from DM1 patients, bridging the gap from fly to human relevance. Remarkably, these defects can be fully remedied by modulating FasII expression, offering new insights into potential therapeutic strategies.

Professor Chan commented: “DM1’s neurological impact has long been overshadowed by its muscular symptoms, but our work shines a light on this critical dimension. By remedying synaptic defects in a simple yet powerful Drosophila disease model, we’ve not only deepened our understanding of the disease but also identified actionable targets that could transform how we protect neurons in DM1 patients. This represents a step toward therapies that address the root causes, rather than just the symptoms.”

This work was supported by The General Research Fund of the Hong Kong Research Grants Council and CUHK’s Gerald Choa Neuroscience Institute. Other key contributors included Senior Lecturer Dr Alex Koon Chun and PhD student Miss Winnie Yeung Ka-yee from the School of Life Sciences.

The full text of the research paper can be found at: https://www.nature.com/articles/s41467-025-67738-w