Research at Tel Aviv University reveals new mechanisms behind autism

Research team at ul Tel Aviv The university recently announced that it has improved understanding of the biological mechanisms underlying genetic autism.

Study published in a peer-reviewed journal Progress of scienceled by prof. Boaz Barak and PhD student Inbar Fischer from the Sagol School of Neuroscience and School of Psychological Sciences at TAU, in cooperation with prof. Ben Maoz from the Department of Biomedical Engineering at the Faculty of Engineering Fleischman TAU and prof. Shani Stern from the University of Haifa Department of Neurobiology.

Barak’s lab is investigating the genetic causes autismincluding mutations in Core3 gene – he explained.

“The impact of these mutations on the functioning of brain neurons has been extensively studied, and we know that the protein encoded by Core3 it plays a key role in binding receptors on the neuron, which is necessary for receiving the chemical signals that neurons use to communicate,” Barak said. “So damaging this gene can disrupt the transmission of messages between neurons, impairing brain development and function. In this study, we sought to shed light on other, previously unknown mechanisms by which mutations in Core3 the gene interferes with brain development, leading to autism.”

The team used a genetically modified mouse model with Core3 a mutation mirroring that in people with this type of autism. They focused on two components of the brain: non-neuronal brain cells (glia), called oligodendrocytes, and the myelin they produce, which has not been extensively studied in this context.

Prof. Boaz Barak (Source: THANKS TO TEL AVIV UNIVERSITY)

They found that the mutation causes a double impairment in brain development and function, Fischer said.

“First, in oligodendrocytes, as in neurons,… Core3 the protein is necessary for the binding and functioning of receptors that receive chemical signals,” she said. “This means that a defective protein associated with autism interferes with the transmission of messages to these important support cells.”

Second, she explained, myelin production is disrupted when oligodendrocyte function and development are impaired.

“Defective myelin does not properly insulate the neuron’s axons, thereby reducing the efficiency of electrical signal transmission between brain cells and the synchronization of electrical activity between different areas of the brain,” she said. “In our model, we found myelin damage in multiple brain regions, which affected the animals’ behavior.”

The team researched potential treatments and hope to develop a therapy for humans. They took oligodendrocytes from mice with the SHANK3 mutation and introduced DNA containing normal humans Core3 sequence.

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Objective

“Our goal was to enable a normal gene to encode a functional protein that, by replacing the defective protein, restores its role in the cell,” Fischer said. “After treatment, the cells expressed normally Core3 proteins, enabling functional receptor binding. Genetic treatment repaired oligodendrocyte communication sites, essential for their proper development and functioning as myelin producers.”

The study identified two new brain mechanisms associated with genetically induced autism: damage to oligodendrocytes and subsequent damage to the myelin they produce, Barak said.

“Recognizing the importance of myelin impairment in autism – whether or not it is associated with Core3 gene or not – opens new paths to understanding the brain mechanisms underlying autism and future treatment methods,” he concluded.

The research was supported by grants to Barak from the Fritz Thyssen Stiftung, the Israel Science Foundation, the Federation of European Biochemical Societies, and the National Institute of Psychobiology in Israel.