Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function

This article speaks on the UNC13A gene that is responsible for information transfer between neurons. It usually contains neurodevelopmental syndrome which is known to cause seizures, tremors and even early (childhood) death. There are three mechanisms that are known to be examined and they consist of “reduction in synaptic strength caused by reduced UNC13A protein expression, increased neurotransmission caused by UNC13A gain-of-function and impaired regulation of neurotransmission by second messenger signalling” (Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function, 2025).  

There are various different types of UNC13A variants that present neurodevelopmental deficiencies. There are three subdivisions of this, let’s start with part A. This is known to compromise variants, sometimes over 50%. This leads to reduced synaptic strength which results in early seizures and developmental delay. Part B are usually heterozygous variants, they increase neurotransmission. This also leads to movement disorders and seizures. Part C is more mild and known to be caused by a heterozygous variant as well. Usually in this case there is little development impairment, seizures and there seems to be a dominant inheritance pattern across generations.

Asadollahi, R., Ahmad, A., Boonsawat, P., Shahanoor Hinzen, J., Lohse, M., Bouazza-Arostegui, B., Sun, S., Utesch, T., Sommer, J. D., Ilic, D., Padmanarayana, M., Fischermanns, K., Ranjan, M., Boll, M., Ka, C., Piton, A., Mattioli, F., Isidor, B., Õunap, K., … Lipstein, N. (2025, October 22). Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function. Nature News. https://www.nature.com/articles/s41588-025-02361-5#Sec10

Account - genecards suite. (n.d.). https://www.genecards.org/cgi-bin/carddisp.pl?gene=UNC13A

Can Monkey’s Cure Autism?

              One out of one hundred and sixty children globally has been diagnosed with autism. In the United States alone, one out of sixty eight children lay within the autism spectrum. This complex brain disorder affects social and motor abilities found in the early stages of children development. Recently, Chinese researchers have developed “transgenic” monkeys that are linked to autistic behaviors. These monkeys introduce a different prospective for studying human autism and may be the model system that will help discover the cure. Mice have been the preferred model for studying any genetic disorders, but they have their limitations. On the contrary, monkeys provide better tools for human research because they are more closely related than mice.

                In humans, a gene known as MECP2 is associated with core symptoms of autism. Whenever this gene is over-expressed or over duplicated, autistic behaviors are the outcome. In order to see if this gene has an effect on animals other than humans, Chinese researchers injected MEPC2 into a monkey’s eggs, allowing them to be fertilized and later transferred to a surrogate monkey. When creating their first transgenic monkey, eight live monkeys were born. Each monkey carried the MEPC2 gene. Although these monkeys acted normal, they lacked normal social behaviors. They did not interact with grooming and frequently moved in repetitive, circular motions. The most interesting behavior they exhibited was increased anxiety when humans were near. The only attribute the monkeys did not display was having a seizure which is a key feature in autistic humans.

            Chinese scientists continue to explore and use brain imaging to target areas for autism-like behavior. If the target can be identified, a gene editing tool called CRISP/Cas9 will be used to control the gene. The only issue researcher’s face right now is the expenses of maintaining the monkeys, but without the monkeys, we may not find a cure.

           In my opinion, I believe that researchers have come one step closer to curing autism. I view myself as an optimist and like think that everything has a cure or solution. Monkeys are human’s closest relatives, so if they can genetically modify the gene that is causing these social behaviors, I believe the same solution could be used with humans. The only problem that concerns me is that the monkeys do not exhibit all features of autism compared to human symptoms, such as seizures. This might be proof that monkeys do not reproduce the human duplication disorder. Through all the hard work and research scientists put into their studies, a solution to autism will be on the way shortly.

Human stem cell-derived neuron transplants reduce seizures in mice

     The Harvard Stem Cell Institute has been working to find ways to treat disease with stem cells. A recent study by Harvard has shown that stem cell transplantation could be a useful way to help epileptics who don't respond well to the current anti-seizure drugs. What they have successfully transplanted in mice are seizure-inhibiting human embryonic stem cell-derived neurons into the brains of mice. The results show that half of the mice no longer had seizures and the other half showed significant drops in frequency of seizures. More research from this project can be viewed in this paper, where the methods are more in depth and results are displayed.

   

     This picture above shows one of the stem cell-derived neurons integrating itself into an affected epileptic brain. I find it interesting how valuable stem cells are to researching new ways to treat disease. I believe they have endless possibilities once we establish ways to mass produce them. The brain is always a touchy subject when it comes to treatments of disease because of all the complications that can come with it, but reading articles like this gives me hope about the future.

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Neurodegeneration Linked To ADP-Ribose

In European news, EMBO.org (European Molecular Biology Organization) reports that researchers have identified an enzyme that removes ADP-ribose modifications from proteins by studying a genetic mutation that causes neurodegenerative disease in humans. These findings, suggest that not only addition but also removal of ADP-ribose from proteins is essential for normal cell function. Poly ADP-ribose or PARP chains play key roles in the repair of cellular DNA damage, and in the control of gene expression and cell death. Pharmacological drugs called PARP inhibitors prevent the addition of ADP-ribose or their polymers to proteins. Several of these drugs are undergoing clinical trials for the treatment of different types of cancers.

A breakthrough in the study came when collaborators from the National Institutes of Health, USA and Ludwig Maximilians University, Munich teamed up with clinical geneticists at the Human Genetics Research Center at St. George's University of London lead by Reza Sharifi. She stated,

“By studying genetic mutations in a group of patients with severe neurodegenerative disease, we found a gene that was mutated in a family that had several cases of severe progressive neurodegenerative and seizure disorder.”

She continued to explain that the product of this gene, named TARG1 (for terminal ADP-ribose protein glycohydrolase), exhibited the long-sought-after enzyme activity that fully removes ADP-ribose from proteins, and was further required for the rapid increase of cells and response to DNA damage.

The full research article can be found at The EMBO Journal.

If you read further into the linked articles it talks about how researchers found a gene that was mutated in a family that had several cases of severe progressive neurodegenerative and seizure disorder. The findings revealed that the attaching and removing chains of ADP-ribose to proteins are important to cell survivability and DNA repair. I find it simply amazing that they can analyze patients with a family history of neurodegeneration to gain a better understanding of this mechanism and perhaps give them a better understanding of what is happening to them and eventually, I believe, how to correct it. They are getting ever closer to finding out the exact enzyme(s) that may be responsible for it.