Comparability of BrdU-labeled cell concentrations within the SVZ of two ADNP mouse fashions, Adnp+/− on ICR background and Tyr mice on C57BL6/NJ background. Credit score: Molecular Psychiatry (2024). DOI: 10.1038/s41380-024-02879-w
Researchers at Tel Aviv College, led by Prof. Illana Gozes, examined the consequences of various mutations within the ADNP protein, which is important for regular mind improvement and growing older, on the mind cells of mice—distinguishing between women and men.
To their shock, they discovered that the faulty protein impacts utterly totally different mechanisms within the two sexes: in males, the harm happens in a mechanism that protects the construction of proteins, which in flip disrupts the method of neurogenesis—the manufacturing of latest mind cells from stem cells—a course of essential for reminiscence and studying. In females, then again, the mechanism that regulates power throughout the cell is impaired, stopping the mind from receiving enough power.
All of those processes are important for sustaining reminiscence and studying capabilities, and their disruption causes important impairment in each sexes, resulting in the event of incurable mind ailments akin to Alzheimer’s, wherein ADNP can be discovered to be faulty.
The analysis was carried out by Prof. Illana Gozes, Dr. Gidon Karmon, and doctoral scholar Man Shapira from the School of Medical and Well being Sciences and the Sagol College of Neuroscience at Tel Aviv College. Further contributors to the examine embrace Prof. Noam Shomron, Dr. Gal Hacohen-Kleiman, and doctoral scholar Maram Ganaiem from the School of Medical and Well being Sciences, Dr. Shula Shazman from the Division of Arithmetic and Pc Science on the Open College, and researchers from the College Hospital of Thessaloniki in Greece.
The examine was revealed within the journal Molecular Psychiatry.
Prof. Gozes acknowledged, “The ADNP protein was found in my lab, and now we have been researching it for a few years. We discovered that it’s important for mind improvement and performs a protecting function in neurodegenerative ailments like Alzheimer’s illness. Moreover, it was discovered that defects within the ADNP gene trigger ADNP syndrome, a uncommon genetic dysfunction related to developmental delays, studying disabilities, and signs 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.”
Utilizing genetic engineering, the researchers established two mouse fashions reflecting totally different types of ADNP syndrome: mice that specific solely half the traditional quantity of ADNP, with just one energetic allele within the DNA as a substitute of two, that are sometimes inherited from each mother and father, and mice with a mutation within the ADNP gene that truncates the protein manufacturing course of, leading to a shorter-than-normal ADNP protein.
Adnp-specific regulated expression in Tyr females. Credit score: Molecular Psychiatry (2024). DOI: 10.1038/s41380-024-02879-w
The researchers word that essentially the most severely affected youngsters with ADNP syndrome are these with the mutation that produces the truncated protein. Moreover, neurogenesis was examined in a management group of wholesome mice.
To trace the course of neurogenesis, a substance was injected into the mice, staining the DNA of mind cells collaborating within the course of. The information have been analyzed utilizing computational bioinformatics strategies, proving that ADNP performs a vital function in neurogenesis. Moreover, a big distinction was discovered between how ADNP capabilities in males versus females.
First, in wholesome mice, neurogenesis was extra energetic in males in comparison with females, whereas in male mice with an ADNP mutation, neurogenesis was lowered to the identical degree as in females. A basic distinction between the sexes was additionally recognized in a further analysis technique: RNA sequencing of all genes within the hippocampus of mice with the truncated ADNP protein.
Prof. Gozes defined, “There was nearly no overlap. The harm to the ADNP protein affected utterly totally different mechanisms in female and male brains. The reason for this phenomenon is that in males, one of many capabilities of ADNP is to control a mechanism that maintains protein construction (unfolded protein response), which in flip 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 a part of the examine, the researchers additionally examined the effectiveness of the experimental drug Davunetide, primarily based on the NAP fragment of the ADNP protein, in treating affected mice. They noticed a optimistic impact in all circumstances, with notably important neurogenesis restoration within the mannequin the place mice had solely half the traditional ADNP ranges.
Prof. Gozes concluded, “Our analysis exhibits that ADNP is intently linked to neurogenesis and that it capabilities in a different way in women and men—a discovering that has additionally emerged in earlier research. Moreover, we discovered that Davunetide, the drug that we found and are growing, is efficient. We purpose to quickly start a scientific trial in youngsters 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.”
Extra data:
Man Shapira et al, ADNP is important for sex-dependent hippocampal neurogenesis, via male unfolded protein response and feminine mitochondrial gene regulation, Molecular Psychiatry (2024). DOI: 10.1038/s41380-024-02879-w
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