Prof. Illana Gozes (Credit Tel Aviv University)
Researchers at Tel Aviv University, led by Prof. Illana Gozes, have uncovered striking differences in how mutations in the ADNP protein—a crucial factor in brain development and aging—affect male and female brain cells. Their study, conducted on mice, revealed that the defective protein disrupts entirely different biological mechanisms in each sex, shedding new light on the complex role of ADNP in neurodegenerative diseases.
To their surprise, the team found that in males, ADNP mutations primarily impair a mechanism responsible for protein structure protection, which in turn disrupts neurogenesis—the process by which stem cells generate new brain cells. Since neurogenesis is essential for learning and memory, this malfunction leads to significant cognitive decline.
In females, however, the defective ADNP protein impacts a different system altogether—cellular energy regulation. This impairment prevents the brain from receiving adequate energy, further compromising cognitive function.
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Both of these disrupted processes—neurogenesis and energy regulation—are critical for maintaining memory and learning, and their failure contributes to severe neurodegenerative conditions, including Alzheimer’s disease, where ADNP mutations have also been implicated.
This groundbreaking research underscores the importance of sex-specific approaches in studying brain disorders and developing targeted treatments, offering a new perspective on the molecular basis of neurodegeneration.
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 prestigious journal Molecular Psychiatry from Nature.
“The ADNP protein was discovered in my lab, and we have been researching it for many years,” Prof. Gozes stated. “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.
