New Links Between EPG5 Mutations, Early Neurodevelopment, and Later Neurodegeneration
A groundbreaking study connects errors in the EPG5 gene, already known for causing the rare neurodevelopmental disorder Vici syndrome, to later-age neurodegenerative conditions such as Parkinson’s disease and dementia. Published in the Annals of Neurology, the research consortium spanning King’s College London, University College London (UCL), the University of Cologne, and the Max Planck Institute for Biology of Ageing expands our understanding of how a single gene can influence brain health across the lifespan.
What is EPG5 and why is it important?
EPG5 plays a pivotal role in autophagy, the cellular recycling process that clears damaged components and recycles them into new cellular parts or disposes of them. The EPG5 protein operates in the final stage of autophagy, helping attach cellular debris to the waste disposal system so it can be removed. When EPG5 is defective, cells struggle to clear damaged proteins and organelles, which can disrupt neural development and maintenance.
From Vici Syndrome to Parkinsonian Changes: The Lifelong Impact
Vici syndrome is a rare, severe neurodevelopmental disorder that typically presents in infancy and can affect multiple organ systems. Yet the new study shows the effects of EPG5 mutations extend beyond early life. Researchers examined clinical and genetic data from 211 individuals worldwide with EPG5 errors and found a spectrum of outcomes—from classic, life-limiting Vici syndrome to milder motor, speech, and learning delays. Even more striking, some patients developed a breakdown of nerve cells during adolescence or early adulthood, accompanied by Parkinson’s disease and dementia-like symptoms.
Brain imaging in a subset of participants revealed iron accumulation, a feature observed in several neurodevelopmental and neurodegenerative disorders, supporting the idea that similar cellular pathways may be involved across ages. This supports a model in which neurodevelopmental and neurodegenerative disorders are mechanistically connected through shared defects in autophagy and protein clearance.
Implications for Research and Treatment
Professor Heinz Jungbluth of King’s College London emphasizes that studying ultra-rare conditions can illuminate common diseases with substantial public health impact. The study underscores how insights from pediatric brain disorders can inform our understanding of adult-onset neurodegenerative diseases like Parkinson’s and dementia. Dr. Reza Maroofian of UCL highlights the value of translational collaboration between basic scientists and clinicians to unravel the mechanisms behind inherited conditions across the lifespan.
The researchers used patient-derived cells and model organisms, including mice and C. elegans, to introduce EPG5 errors. These experiments demonstrated that dysfunctional autophagy leads to the accumulation of proteins associated with Parkinson’s disease, offering a plausible mechanistic link between early developmental disturbances and later neurodegenerative processes. This work points to a continuum of disease rather than discrete, age-bound categories.
How this Shapes Future Therapies
Understanding that autophagy disruption can drive both early brain development problems and late-life neurodegeneration opens potential avenues for intervention. Therapies targeting autophagy pathways, or strategies designed to enhance cellular clearance mechanisms, could potentially benefit individuals with EPG5-related conditions at any life stage. While much work remains before such approaches reach clinical practice, this research provides a critical framework for developing treatments that address shared cellular drivers of disease.
About the Study
The largest study to date examining EPG5 mutations involved 211 participants from around the world. By integrating genetic data with clinical phenotypes and neuroimaging, the team demonstrated the breadth of EPG5’s impact and its links to Parkinson’s disease and dementia in adolescence and adulthood. The work underscores the interconnected nature of neurodevelopmental and neurodegenerative disorders and strengthens the case for a life-course approach to studying brain disease.
Expert Commentary
Dr. Manolis Fanto of King’s College London notes that this project exemplifies the synergy between basic and clinical neuroscience. The findings advocate for continued cross-disciplinary collaboration to decipher how a single gene modulates crucial cellular processes across life stages, with the ultimate aim of improving outcomes for patients and families affected by these conditions.
Conclusion
The discovery that EPG5 mutations can contribute to both Vici syndrome and later neurodegenerative conditions marks a significant advance in neuroscience. By revealing a shared autophagy-related mechanism, this research not only broadens our understanding of disease pathways but also strengthens the foundation for future therapies that address the root cellular drivers across the lifespan.
