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Zinc could ease brain damage caused by a rare genetic disorder
Pediatric encephalopathies of genetic origin cause severe motor and mental disabilities from birth. One of these diseases, first identified in 2013, is caused by mutations in the GNAO1 gene. To understand the finer details of the resulting disruptions, scientists at the University of Geneva (UNIGE) conducted atomic, molecular and cellular analyses. They discovered that a mutation in GNAO1 causes one amino acid to be replaced by another in the protein sequence. This is enough to disrupt the activation and deactivation mechanism of the encoded protein, thereby altering the ability of neurons to correctly communicate with their environment. A simple zinc molecule that...
Zinc could ease brain damage caused by a rare genetic disorder
Pediatric encephalopathies of genetic origin cause severe motor and mental disabilities from birth. One of these diseases, first identified in 2013, is caused by mutations in the GNAO1 gene. To understand the finer details of the resulting disruptions, scientists at the University of Geneva (UNIGE) conducted atomic, molecular and cellular analyses. They discovered that a mutation in GNAO1 causes one amino acid to be replaced by another in the protein sequence. This is enough to disrupt the activation and deactivation mechanism of the encoded protein, thereby altering the ability of neurons to correctly communicate with their environment. A simple zinc molecule, commonly used in other contexts, could at least partially restore the function of the protein affected by these mutations. These results, published in the journal Science Advances, offer hope for a treatment that could change the lives of patients and their families.
Children with mutations in the GNAO1 gene show significant clinical disorders: delayed intellectual and motor development, uncontrollable movements and more or less severe epilepsy, sometimes accompanied by brain damage and atrophy. GNAO1 encodes a protein called “Gαo,” which is one of the most important building blocks of neuronal cells. “This mutation is heterozygous dominant, which means that one of the two copies of the gene is functional and the other is mutated,” explains Vladimir Katanaev, professor in the Department of Cell Physiology and Metabolism at the UNIGE Faculty of Medicine. who led this research. “Even if neurons have only half of normal proteins, the results are devastating for neurological development.”
A single amino acid modified
Functional Gαo proteins are activated when bound to the nucleotide called GTP and are then deactivated by hydrolysis. This allows the proteins to follow an activation and deactivation cycle necessary for cell function. Mutations in the GNAO1 gene result in one amino acid in Gαo being replaced by another. These mutated proteins are activated very quickly but are unable to perform hydrolysis. You are therefore trapped in a permanent state of activation. “These mutations were found to indirectly affect a crucial amino acid for GTP hydrolysis: glutamine 205. Normally, this glutamine is structurally located opposite GTP, allowing hydrolysis.” However, in the event of a pathological mutation, this glutamine is displaced: this structural distance prevents this mechanism from taking place," explains Vladimir Katanaev. By disrupting interactions with cell membrane proteins, these mutations alter the ability of neurons to communicate with their environment.
A molecule that has been known for decades
The scientists based their further study on these initial basic results. “Ultimately, our goal is to find a treatment that could alleviate the symptoms of the disease and improve the quality of life for patients and their families.” To this end, the research team conducted a high-throughput screening of thousands of approved drugs with the idea of identifying a molecule capable of reactivating hydrolysis. "In fact, in rare diseases there is usually no way to develop a completely new molecule. Instead, repurposing already available, approved and safe drug molecules can be a successful strategy." , adds Vladimir Katanaev.
One molecule, zinc pyrithione, stood out: it corrects the loss of intracellular interactions by bringing glutamine 205 close to its normal structural position, allowing GTP hydrolysis to occur.
This is an old antifungal and antibacterial drug that is used in cream form for certain skin diseases. We took the analysis a step further to see whether this molecule was fully or partially effective. It turns out that the zinc ion is effective here. “It is very easy to find in any pharmacy and is already approved for the treatment of mild depression, insomnia and even some developmental disorders in children.”
Vladimir Katanaev, Professor, Department of Cell Physiology and Metabolism, UNIGE Faculty of Medicine
A flight model to confirm these results
To confirm this result, the research team used an innovative animal model: the Drosophila fly. “We modified the genome of flies to reproduce the mutation of the GNAO1 gene while maintaining a normal copy of the gene like in humans,” explains Mikhail Savitskiy, a researcher in Vladimir Katanaev's laboratory and a specialist in disease modeling in Drosophila. “The flies had mobility problems and a shortened lifespan.” However, adding zinc to their diet for life from the larval stage almost completely eliminated these symptoms. “This result is truly astonishing, especially since zinc is a very safe, well-tolerated and inexpensive substance.” The first patient trials look promising; Clinical studies should now be carried out to assess whether an improvement can be measured in the long term.
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Reference:
Larasati, Y. A., et al. (2022) Restoration of GTPase activity and cellular interactions of Gαo mutants by Zn2+ in GNAO1 encephalopathy models. Scientific advances. doi.org/10.1126/sciadv.abn9350.
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