Pediatric encephalopathies of genetic origin cause severe motor and intellectual 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 disturbances, scientists at the University of Geneva (UNIGE) in Switzerland performed atomic, molecular and cellular analyses. They discovered that zinc could treat this disease.

The researchers found that a mutation in GNAO1 leads to the substitution of one amino acid for another in the protein sequence. This is enough to disrupt the mechanism for turning the encoded protein on and off, thereby altering the ability of neurons to communicate properly with their environment.

Zinc could treat, at least in part, the protein affected by these mutations. These results bring hope for a potentially life-changing treatment for patients and their families.

The study was published in the journal Science Advances.

Zinc could treat rare disease

Children with GNAO1 gene mutations show significant clinical disorders: delayed intellectual and motor development, uncontrollable movements, as well as more or less severe epilepsy, sometimes accompanied by brain damage and atrophy. GNAO1 encodes a protein called “Gαo”, which is one of the most essential building blocks of neuronal cells.

“This mutation is heterozygous dominant, meaning that one of the two copies of the gene is functional and the other is mutated. Even if neurons have half of the normal proteins, the effects in neurodevelopment are devastating”, explains Vladimir Katanaev, professor at the Department of Physiology and Cellular Metabolism at UNIGE Faculty of Medicine, who led this research.

Mutant proteins

Functional Gαo proteins are activated when bound to the nucleotide called GTP, then inactivated by hydrolysis. This allows the proteins to undergo a cycle of activation and deactivation necessary for the cell to function, he writes Medical Xpress.

Mutations in the GNAO1 gene lead to the replacement of one amino acid in Gαo by another. These mutant proteins are activated very quickly but are unable to perform hydrolysis. Thus they are trapped in a permanent state of activation.

“These mutations were found to indirectly affect an amino acid crucial for GTP hydrolysis: glutamine 205. Normally, this glutamine is located structurally opposite to GTP, which allows hydrolysis. However, this glutamine is displaced in the case of a pathological mutation: this structural distance prevents the mechanism from working”, explains Vladimir Katanaev.

By disrupting interactions with cell membrane proteins, these mutations alter the ability of neurons to communicate with their environment.

Zinc could treat the disease and improve patients’ quality of life

The scientists based the rest of their study on these first fundamental results. “Ultimately, our goal is to try to find a treatment that limits the symptoms of the disease and improves the quality of life for patients and their families,” the researchers said.

To do this, the research team performed a high-throughput screening of thousands of approved drugs hoping to identify a molecule capable of reactivating hydrolysis.

“In rare diseases, there is usually no way to develop a completely new molecule. Reusing 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 location, allowing GTP hydrolysis.

“This is an old antifungal and antibacterial medicine used in cream form for certain skin conditions. We took the analysis a step further to see if all or only part of this molecule was effective. It has been proven that the zinc ion is the effective one. Very easy to find in any pharmacy, it is already approved for the treatment of mild depression, insomnia and even in some developmental disorders in children,” says Vladimir Katanaev.

Vinegar Muscles

To confirm this result, the research team used an innovative animal model: the Drosophila fly. “We modified the housefly genome to copy the GNAO1 gene mutation while keeping a normal copy of the gene, as in humans,” explains Mikhail Savitskiy, a researcher in Vladimir Katanaev’s lab and a specialist in Drosophila disease modeling.

“The muscles had mobility problems and a reduced lifespan,” says the researcher. However, zinc could treat the problem if added to the diet throughout life, starting from the larval stage, allowing almost complete elimination of symptoms.

“This result is really amazing, especially since zinc is a very safe, well-tolerated and inexpensive substance,” says Savitskiy. The first patient studies look promising; clinical trials are to be conducted to assess whether the improvement is long-term.

Leave A Reply