Rare genetic syndrome affects male and female brains in distinct ways microbiologystudy

Researchers at Tel Aviv University, led by Prof. Illana Gozes, examined the effects of different mutations in the ADNP protein, which is essential for normal brain development and aging, on the brain cells of mice—distinguishing between males and females.

To their surprise, they found that the defective protein affects completely different mechanisms in the two sexes: in males, the damage occurs in a mechanism that protects the structure of proteins, which in turn disrupts the process of neurogenesis—the production of new brain cells from stem cells—a process crucial for memory and learning. In females, on the other hand, the mechanism that regulates energy within the cell is impaired, preventing the brain from receiving sufficient energy.

All of these processes are essential for maintaining memory and learning functions, and their disruption causes significant impairment in both sexes, leading to the development of incurable brain diseases such as Alzheimer’s, in which ADNP is also found to be defective.

The research was conducted by Prof. Illana Gozes, Dr. Gidon Karmon, and doctoral student Guy Shapira from the Faculty of Medical and Health Sciences and the Sagol School of Neuroscience at Tel Aviv University. Additional contributors to the study include Prof. Noam Shomron, Dr. Gal Hacohen-Kleiman, and doctoral student Maram Ganaiem from the Faculty of Medical and Health Sciences, Dr. Shula Shazman from the Department of Mathematics and Computer Science at the Open University, and researchers from the University Hospital of Thessaloniki in Greece.

The study was published in the journal Molecular Psychiatry.

Prof. Gozes stated, “The ADNP protein was discovered in my lab, and we have been researching it for many years. We found that it is critical for brain development and plays a protective role in neurodegenerative diseases like Alzheimer’s disease. Additionally, it was found that defects in the ADNP gene cause ADNP syndrome, a rare genetic disorder associated with developmental delays, learning disabilities, and symptoms of autism.

“In parallel, we are developing the experimental drug Davunetide, which is based on a fragment of the ADNP protein. In this study, we aimed to examine whether ADNP is involved in the process known as ‘neurogenesis’—the formation of new neurons from stem cells in the adult brain, a process essential for memory and learning. We focused on the hippocampus, a brain region crucial for memory, in adult mice.”

Using genetic engineering, the researchers established two mouse models reflecting different forms of ADNP syndrome: mice that express only half the normal amount of ADNP, with only one active allele in the DNA instead of two, which are typically inherited from both parents, and mice with a mutation in the ADNP gene that truncates the protein production process, resulting in a shorter-than-normal ADNP protein.

The researchers note that the most severely affected children with ADNP syndrome are those with the mutation that produces the truncated protein. Additionally, neurogenesis was examined in a control group of healthy mice.

To track the course of neurogenesis, a substance was injected into the mice, staining the DNA of brain cells participating in the process. The data were analyzed using computational bioinformatics methods, proving that ADNP plays a crucial role in neurogenesis. Furthermore, a significant difference was found between how ADNP functions in males versus females.

First, in healthy mice, neurogenesis was more active in males compared to females, while in male mice with an ADNP mutation, neurogenesis was reduced to the same level as in females. A fundamental difference between the sexes was also identified in an additional research method: RNA sequencing of all genes in the hippocampus of mice with the truncated ADNP protein.

Prof. Gozes explained, “There was almost no overlap. The damage to the ADNP protein affected completely different mechanisms in male and female brains. The explanation for this phenomenon is that in males, one of the functions of ADNP is to regulate a mechanism that maintains protein structure (unfolded protein response), which in turn regulates neurogenesis.

“In fact, the ADNP gene is a master regulator of this entire mechanism in male brains, and when it is defective, the process is significantly impaired. In females, however, the ADNP protein enters the mitochondria—the cell’s energy powerhouse—and when the mutation alters the protein’s structure, less ADNP is able to enter the mitochondria. As a result, energy production in the cell is likely impaired, disrupting brain function, which requires a large amount of energy.”

As part of the study, the researchers also tested the effectiveness of the experimental drug Davunetide, based on the NAP fragment of the ADNP protein, in treating affected mice. They observed a positive effect in all cases, with particularly significant neurogenesis recovery in the model where mice had only half the normal ADNP levels.

Prof. Gozes concluded, “Our research shows that ADNP is closely linked to neurogenesis and that it functions differently in males and females—a finding that has also emerged in previous studies. Additionally, we found that Davunetide, the drug that we discovered and are developing, is effective. We aim to soon begin a clinical trial in children with ADNP syndrome (ADNP deficiency).

“We hope that in the future, the drug will also help Alzheimer’s patients—in whom we previously found sex-based differences—as well as other neurodegenerative diseases where ADNP is impaired. Notably, the rare and incurable disease Progressive Supranuclear Palsy (PSP), which has pathological similarities to Alzheimer’s disease, showed significant improvement in women treated with Davunetide in our previous clinical study.”