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Summary: Scientists have discovered that mutations in the EPG5 gene, known to cause the rare childhood disorder Vici syndrome, also increase the risk of Parkinson’s disease and dementia later in life. The gene plays a crucial role in autophagy, the process by which cells remove damaged material.
When this system fails, harmful proteins build up, damaging nerve cells over time. Study reveals a direct biological link between early neurodevelopmental disorders and late-onset neurodegenerative diseases, offering hope for shared therapeutic targets.
Key facts:
Shared mechanism: EPG5 mutations disrupt autophagy, linking rare childhood disorders to adult neurodegeneration. Wider effects: People with EPG5 errors may develop Parkinson’s or dementia in adolescence or adulthood. Therapeutic perspective: The findings highlight how the study of ultra-rare diseases can guide treatments for common neurological conditions.
Source: King’s College London
According to new research, errors in a gene known to cause a serious neurodevelopmental disease in infants are also linked to the development of Parkinson’s disease in adolescence and adulthood.
The study, published in Annals of Neurology, looked at a gene called EPG5. Errors in this gene are already known to cause Vici syndrome, a rare and serious inherited neurodevelopmental disease that occurs early in life and affects multiple organ systems.
Now, researchers from King’s College London, University College London (UCL), the University of Cologne and the Max Planck Institute for the Biology of Aging have discovered that errors in the same gene are linked to changes in nerve cells that lead to more common age-related conditions such as Parkinson’s disease and dementia.
Professor Heinz Jungbluth, Professor of Pediatric Neurology at King’s College London and senior author and co-senior author of the study, said: “This research, supported by patient organisations, was motivated by our previous observation of an apparent increased risk of Parkinson’s disease in relatives of children with Vici syndrome, after our team at King’s discovered that EPG5 was a driving factor. of this condition.
“Our work shows that, although rarely considered a priority, research into (ultra) rare diseases such as Vici syndrome (where fewer than 10 children are currently known to have this condition in the UK) can provide vital information on much more common disorders and have important public health benefits.
“Understanding the causes of these devastating and often life-limiting diseases is essential for the development of therapies and therefore offers hope to patients and their families.”
In the largest study of its kind to date, the team of scientists analyzed clinical and genetic data from 211 individuals from around the world with rare errors in EPG5. They found that the effects of these genetic errors are broader and more variable than previously known: while some individuals were identified with life-limiting forms of Vici syndrome before or shortly after birth, others showed much milder symptoms, including delays in movement, speech and learning.
The researchers also found that some of the patients included in the study developed nerve cell breakdown in adolescence or early adulthood that led to Parkinson’s disease and dementia. The brain scans analyzed in some cases showed additional accumulation of iron in the brain, a feature of other closely related neurodevelopmental disorders.
Dr Reza Maroofian, co-first author of the study from UCL’s Queen Square Institute of Neurology, said: “Our findings link EPG5 dysfunction to Parkinson’s disease, highlighting how neurodevelopmental and neurodegenerative disorders may be mechanistically interconnected and add to a growing list of such conditions.
“This study highlights how insights into rare pediatric brain disorders can help understand our most common adult-onset neurodegenerative diseases, such as Parkinson’s and dementia.”
The EPG5 gene is involved in an important cellular process called autophagy, where the cell breaks down unwanted or damaged components and recycles them into new parts or throws them away. The protein produced by EPG5 is involved in the last stage of this process: joining the pieces for removal to the cell’s waste removal unit for removal from the cell.
To explore the biology behind their findings, the researchers used cells derived from patients and model organisms, including mice and the tiny roundworm C. elegans, and introduced errors into EPG5.
These experiments demonstrated that genetic errors in the gene impair the cell’s ability to remove damaged components from the cell, leading to the accumulation of proteins closely associated with Parkinson’s disease.
Professor Jungbluth, who is also a consultant pediatric neurologist at Evelina London Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, said: “Using the example of EPG5, our findings suggest a life-long continuum of early-onset and late-onset neurodegenerative disorders, and more specifically a link “intriguing between aberrant nerve development and degeneration linked in the same fundamental cell.” “Preserved mechanism in different species.”
Dr Manolis Fanto, Professor of Functional Genomics at King’s College London and co-senior author of the study, added: “This project highlights the importance of collaboration between basic and clinical neuroscientists to unravel the complex mechanistic consequences of inherited genetic conditions at all stages of life.”
The study provides new insight into how errors in autophagy can underpin a variety of lifelong neurological conditions and may help pave the way for future treatments targeting these shared disease drivers.
Key questions answered:
A: Vici syndrome is a rare inherited neurodevelopmental disorder caused by mutations in the EPG5 gene. It affects multiple organ systems, including the brain, muscles, heart and immune system, causing severe developmental delays and other complications that often appear early in life.
A: Errors in EPG5, which have long been known to cause Vici syndrome in babies, are also linked to Parkinson’s disease and dementia later in life.
A: EPG5 controls how cells remove damaged material; When disrupted, proteins accumulate and damage neurons, leading to neurodegeneration.
A: It bridges the gap between rare pediatric brain disorders and widespread diseases in adults, revealing shared biological pathways that could be targeted by new treatments.
About this news about Parkinson’s disease, Vici syndrome and genetic research
Author: Joanna Dungate
Source: King’s College London
Contact: Joanna Dungate – King’s College London
Image: Image is credited to Neuroscience News.
Original research: Open access.
“Mutations in the key autophagy anchoring factor EPG5 link neurodevelopmental and neurodegenerative disorders, including early-onset parkinsonism” by Heinz Jungbluth et al. Annals of neurology
Abstract
Mutations in key autophagy anchoring factor EPG5 link neurodevelopmental and neurodegenerative disorders, including early-onset parkinsonism
Aim
Autophagy is a fundamental biological pathway with vital functions in intracellular homeostasis. During autophagy, defective cargo, including mitochondria, is directed to lysosomes for removal and recycling.
Truncating recessive variants in the autophagy gene EPG5 have been associated with Vici syndrome, a severe, early-onset neurodevelopmental disorder with widespread multisystem involvement. Here, we aimed to delineate the extended spectrum of age-dependent, EPG5-related diseases.
Methods
We investigated the clinical, radiological and molecular characteristics of the largest cohort of EPG5-related patients identified to date, complemented by experimental investigation of cellular and animal models of EPG5 defects.
Results
Through a global collaboration, we identified 211 patients, 97 of them unpublished, with recessive variants of EPG5. The phenotypic spectrum ranged from prenatally lethal presentations to milder isolated neurodevelopmental disorders.
A novel mouse model with Epg5 activation of a recurrent missense variant of EPG5 exhibited motor deficits and defective autophagy in brain areas particularly relevant to neurological disorders in milder presentations.
New age-dependent neurodegenerative manifestations in our cohort included adolescent-onset parkinsonism and dystonia with cognitive impairment and myoclonus. Radiological features suggested an emerging continuum with brain iron accumulation disorders.
Patient fibroblasts showed defects in PINK1-Parkin-dependent mitophagic clearance and α-synuclein overexpression, indicating a cellular basis for the observed neurodegenerative phenotypes. In Caenorhabditis elegans, deletion of EPG5 caused motor impairments, defective mitophagic clearance, and changes in mitochondrial respiration comparable to observations in deletion of parkinsonism-related genes in C. elegans.
Interpretation
Our findings illustrate a continuum of lifelong neurological diseases associated with pathogenic EPG5 variants, linking neurodevelopmental and neurodegenerative disorders through the common denominator of defective autophagy.
