ROS and apoptosis-related markers are altered throughout the cortex of cKO mice compared to controls. The mRNA levels of ROS-related genes and protein levels in cortex homogenates of cKO mice compared to control were examined. A Hypoxia-related properties were examined by measuring Hif1a mRNA transcript levels in cortex homogenates of cKO and control mice. In P1 mice, cKO showed a significantly higher value Hif1a mRNA levels (*P. = 0.04), but not in P30 (ns), compared to controls. b Whole cortex homogenates of P1 and P30 cKO compared to control samples were subjected to immunoblotting, using Hif1a antibody, and showed no significant differences in protein levels. vs Representative Hif1a immunoblot results. d The ROS inhibition properties were examined by measuring Pgc1a mRNA levels in cortex homogenates of cKO and control mice. In P1 cKO mice, no significant differences (ns) were observed, while in P30 cKO mice, the expression level of Pgc1a compared to controls (*P. = 0.01). e Apoptotic properties were examined by measuring JunemRNA transcript levels in cortex homogenates of cKO and control mice. In P1 mice, cKO showed a significantly higher value June mRNA levels (*P.= 0.01), but not in P30 (ns), compared to controls. Statistical significance was determined by A Mann-Whitney test and b, d, e unpaired t -test. A not= 8 control mice, not= 7 cKO mice, not= 6 control mice, not= 8 cKO mice. b not= 8 control mice, not= 8 cKO mice. d not= 12 control mice, not= 12 cKO mice, not= 7 control mice, not= 8 cKO mice. e not= 8 control mice, not= 7 cKO mice, not= 11 control mice, not= 13 cKO mice. Values represent means ± SEM. ns not significant. Credit: Communication biology(2023). DOI: 10.1038/s42003-023-05612-5
In a first, researchers at Tel Aviv University have discovered that the production and regulation of mitochondrial organelles in brain nerve cells (neurons) is significantly altered by deletion of a gene called Gtf2i, one of the 25 genes deleted in Williams syndrome.
This deficiency is known to cause functional incapacity of nerve cells and may be the cause of neurodevelopmental pathologies such as Williams syndrome and other conditions associated with the Gtf2i gene.
The discovery is the result of the efforts of a team of researchers led by Professor Boaz Barak of the Sagol School of Neuroscience and the School of Psychological Sciences at Tel Aviv University and Ariel Nir-Sade, for whom this revolutionary research constitutes his doctoral thesis.
“We have 100 billion nerve cells in the brain that are essential for maintaining brain activity,” explains Professor Barak. “To do this, these cells need energy. This energy is produced in the mitochondrial organelle; therefore, a problem with mitochondrial function will lead to a problem with the functioning of the cell.”
“Today we understand that mitochondria are ‘responsible’ for a variety of neurological pathologies, from neurodevelopmental disorders like Angelman syndrome and autism to neurodegenerative diseases like Alzheimer’s and Parkinson’s. These are all disorders which involve, among other things, abnormal functioning of the mitochondria.
In Professor Barak’s laboratory, researchers focus on a genetic syndrome called Williams syndrome, which results from the defective expression of around 25 genes. Until now, it was not clear why the nerve cells of people with the syndrome were damaged, that is, what the correlation was between the defective expression of these genes and the impaired brain functions that occur. resulted.
“Williams syndrome is a relatively rare developmental neurogenetic syndrome,” says Nir-Sade. “Individuals with this condition are born with multisystem deficits from birth, cognitive, motor and behavioral problems, but perhaps their most distinctive trait is their difficulty regulating social behavior. This is why it is called often “love syndrome” – these individuals tend to display considerable affection and a strong desire for social interaction.
Among the 25 genes that are not correctly expressed in individuals with Williams syndrome, Professor Barak and Nir-Sade’s research focused on the Gtf2i gene. This gene is essential to understanding the syndrome because it codes for a transcription factor, a protein responsible for regulating many other genes and, as they discovered during their research, regulating the expression of genes involved in mitochondria.
In their quest to understand the role of this gene in nerve cells in the brain, Tel Aviv University researchers used genetic engineering techniques to compare the mitochondrial structure of nerve cells with and without the Gtf2i gene.
Typically, mitochondria work together in the form of a network, but in the absence of the Gtf2i gene, the process of network formation is not properly regulated. As a result, network formation is impaired, mitochondria have difficulty functioning, and abnormal substances accumulate inside the cell.
“First, we extracted nerve cells from the brains of animal models with Williams syndrome and cultured them,” explains Nir-Sade. “We compared cultures of normal nerve cells to those in which the Gtf2i gene had been deleted by genetic engineering. We looked at each individual cell and demonstrated how the mitochondrion has difficulty growing and functioning without this gene.”
“Secondly, with the help of the laboratory of Dr. Asaf Marco at the Hebrew University of Jerusalem, we wanted to see if the fundamental mechanism that we had discovered in animal model cultures would also be valid for human subjects. We examined brain tissue obtained from people born with Williams syndrome whose brains were donated to scientific research after their death.”
“We observed that our findings also apply to the human brain: in people with Williams syndrome, mitochondria do not develop and function properly and, as a result, toxic materials accumulate inside them. of the nerve cell, thus affecting their effectiveness.”
“These results are of clinical importance,” adds Professor Barak. “They improve our understanding of what is needed to improve neuronal function in the brain, for example improving mitochondrial function or reducing the expression level of substances that accumulate in the nerve cells of people with Williams syndrome. Biomedical research is devoting considerable effort and resources toward understanding mitochondrial diseases, and significant progress is being made in this area.
“It is plausible that in the future a drug will be developed to improve mitochondrial function in other diseases, such as Alzheimer’s disease, and that, based on our research, they will also know how to adapt the drug to Williams syndrome, with the aim of improving mitochondrial function in this specific context.
The work is published in the journal Communication biology.
More information:
Ariel Nir Sade et al, Neuronal deletion of Gtf2i modifies mitochondrial and autophagic properties, Communication biology(2023). DOI: 10.1038/s42003-023-05612-5
Provided by Tel Aviv University
Quote: Research finds one of the deleted genes linked to Williams syndrome is responsible for mitochondrial function in the brain (January 10, 2024) retrieved January 10, 2024 from
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