Scientific breakthrough in the study of neurological disorders

Williams syndrome is a developmental disorder that affects many parts of the body and is characterized by mild to moderate intellectual disability or learning problems, unique personality characteristics, and distinctive facial features – including a broad forehead, puffiness around the eyes, a flat bridge of the nose, full cheeks, and a small chin. 

In a first, Tel Aviv University (TAU) researchers have discovered that the production and regulation of mitochondrial organelles in the brain’s neurons becomes significantly impaired with the deletion of a gene called Gtf2i – one of the 25 genes deleted in Williams syndrome.

Many affected people have dental problems such as teeth that are small, widely spaced, crooked, or missing, and cardiovascular problems – as well as an unusual star-like pattern in the iris of the eye.

Patients typically have difficulty with visual-spatial tasks such as drawing and assembling puzzles, but they tend to do well on tasks that involve spoken language, music, and learning by rote memorization. 

Affected individuals have outgoing, engaging personalities and tend to have a unique ability to connect with others and form strong bonds, making them appear very happy and engaging.

Additionally, people with Williams syndrome often have a keen interest in music. They may have a talent for it, contributing to their overall well-being and happiness.

The research for this rare syndrome can impact Alzheimer's research

The syndrome, which affects an estimated one in 7,500 to 18,000 people, is caused by the loss of material from a specific region of chromosome number seven. The deleted region includes 25 to 27 genes, and researchers believe that a loss of several of these genes contributes to the characteristic features of this disorder.

Most cases of Williams syndrome are not inherited. The chromosomal alteration usually occurs as a random event during the formation of the eggs or sperm in a parent of an affected individual. These cases occur in people with no history of the disorder in their family. 

The TAU discovery emerged from the efforts of a team of researchers spearheaded by Prof. Boaz Barak of the Sagol School of Neuroscience and the School of Psychological Sciences and Ariel Nir-Sade, for whom this groundbreaking research constitutes her doctoral thesis. 

Therefore, a problem with the mitochondrial function will lead to a problem with the functioning of the cell. Today, we understand that the mitochondria are ‘to blame’ for a variety of neurological pathologies, from neurodevelopmental disorders such as Angelman syndrome and autism to neurodegenerative diseases like Alzheimer’s and Parkinson’s – these are all disorders that involve, among other things, abnormal functioning of the mitochondria.”

In Barak’s lab, the researchers focussed on Williams syndrome. Until now, it was not clear why the nerve cells of those with the syndrome are damaged – that is, what the correlation was between the faulty expression of these genes and the resultant impairment of brain function.

“Williams syndrome is a relatively rare developmental neurogenetic syndrome,” explains Nir-Sade. “Individuals with this condition are born with multisystemic deficits from birth, but perhaps their most distinguishing trait is their difficulty in regulating social behavior. That is why it’s often referred to as the ‘love syndrome’ – these individuals tend to exhibit considerable affection and a strong desire for social interaction.”

Among the 25 genes that are not properly expressed in individuals with Williams syndrome, Barak and Nir-Sade’s research has focused on the Gtf2i gene. This gene is key for understanding the syndrome, as it encodes a transcription factor – a protein that is responsible for regulating numerous other genes and, as they discovered in their research, for regulating the expression of genes involved in mitochondria. 

In their pursuit to understand the role of this gene in the brain’s nerve cells, the researchers used genetic engineering techniques to compare the mitochondrial structure in 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 forming the network is not properly regulated. As a result, the formation of the network is impaired, the mitochondria have difficulty functioning, and abnormal substances accumulate inside the cell.

“In the first stage, we extracted nerve cells from the brains of animal models of Williams syndrome and grew them in culture,” Nir-Sade explained. “We compared normal nerve cell cultures to those in which the Gtf2i gene had been deleted using genetic engineering. We were able to examine the individual cell and demonstrate how the mitochondrion has difficulty developing and functioning without this gene. 

In the second stage, with the help of Dr. Asaf Marco’s laboratory at the Hebrew University of Jerusalem, we wanted to see if the basic mechanism we discovered in animal model cultures would also be valid for human subjects. We examined brain tissue obtained from individuals born with Williams syndrome in which their brains were donated to scientific research after their deaths. 

We observed that our findings hold true for human brains as well: In individuals with Williams syndrome, the mitochondria do not develop and function properly, and as a result, toxic material accumulates inside the nerve cell, thereby affecting their efficiency.”

“These findings hold clinical importance,” Barak concluded. “They improve our understanding of what is required to improve neural function in the brain – for example, improving mitochondrial function or reducing the level of the expression of the substances that accumulate in the nerve cells of people with Williams syndrome. 

Biomedical research dedicates substantial effort and resources toward understanding mitochondrial diseases, and significant progress is underway in this area. 

It’s plausible that in the future, a drug will be developed to improve mitochondrial function in other conditions such as Alzheimer’s, and based on our research, they will know how to adapt the drug for Williams syndrome as well, with the aim of improving mitochondrial function in this specific context.”