2023-06-28 08:19:49
Faced with childhood neurodevelopmental disorders, how to get out of the therapeutic impasse? The answer may well lie in the genes of the proteasome, an intracellular machinery responsible for removing defective proteins from the cell. A research team from Inserm, CNRS, Nantes University and Nantes University Hospital, within the Institut du thorax and in collaboration with international teams, studied the genome of 23 children with neurodevelopmental disorders. She thus highlighted fifteen mutations of the PSMC3 gene of the proteasome likely to be involved in their disease. This work, published in Science Translational Medicine, opens up new research perspectives to better understand these diseases and identify treatments.
The origin of a neurodevelopmental disorder in the child still remains today difficult to identify and patients and their families often face years of diagnostic wandering. A research team from the thorax institute (Inserm – CNRS – Nantes University – Nantes University Hospital)led by Stéphane Bézieau, head of the medical genetics department at Nantes University Hospital, has been working for several years on the genetics of neurodevelopmental disorders in children.
His work notably led to the identification of the role of a gene called PSMD12 in an infantile neurodevelopmental disease. This gene is expressed in a large complex of proteins located in the cells and called the proteasome.
The proteasome functions as a kind of “garbage collector” within the cell. By allowing theelimination of defective proteins it contains, it plays a decisive role in a large number of cellular processes. The alterations that may appear in some of the genes that make it up are likely to impact its ability to degrade defective proteins. Their accumulation results in the appearance of a wide variety of pathologies.
Exploring the links between proteasome gene mutations and neurodevelopmental diseases
In new work (1), in collaboration with international teams, the research team has continued to explore the links between mutations in proteasome genes and neurodevelopmental diseases. This time she was more specifically interested in proteasome PSMC3 gene and its implication in neurodevelopmental disorders of 23 young European, American and Australian patients with neurological symptoms (speech delay, intellectual disability, or behavioral problems) frequently associated with facial abnormalities and malformations of the skeleton, heart, and other organs. Thanks to whole genome sequencing of these patients, the researchers have thus highlighted fifteen gene mutations PSMC3 likely to explain the origin of the symptoms.
“It quickly became apparent that the cells of patients carrying a faulty PSMC3 gene were literally overloaded with proteins that were useless and toxic to them”, explains Frédéric Ebstein, Inserm researcher and first author of the study. He compares this phenomenon to that observed in certain age-related neurodegenerative diseases, such as Alzheimer’s or Parkinson’s disease.
“The discovery of the involvement of a second gene in childhood neurodevelopmental disorders sheds new light on this group of rare diseases that were still unknown until recently.“, specifies the researcher Sébastien Küry, engineer at the University Hospital of Nantes, who co-signed this work. “This work, together with the team’s recent discovery of other genes implicated [mais encore non publiés à ce jour, ndlr.]opens up major perspectives in the understanding of this group of neurodevelopmental diseases as well as treatment perspectives”he concludes.
(1) This work is financially supported by the National Research Agency (ANR), the European Union (European Joint Program on Rare Diseases) and the insurance company AXA
Crédit photo : © ADN double hélice – National Human Genome Research Institute, National Institutes of Health.
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