A research team at Tel Aviv University has expanded the understanding of the biological mechanisms underlying genetic autism, the university recently announced.
The study, published in the peer-reviewed journal Science Advances, was led by Prof. Boaz Barak and PhD student Inbar Fischer from the Sagol School of Neuroscience and the School of Psychological Sciences at TAU, in collaboration with Prof. Ben Maoz from TAU’s Department of Biomedical Engineering in the Fleischman Faculty of Engineering and Prof. Shani Stern from the University of Haifa’s Department of Neurobiology.
Barak’s lab researches genetic causes of autism, including mutations in the SHANK3 gene, he explained.
“The impact of these mutations on the function of brain neurons has been extensively studied, and we know that the protein encoded by SHANK3 plays a central role in binding receptors in the neuron, which is essential for receiving chemical signals by which neurons communicate,” Barak said. “Thus, damage to this gene can disrupt message transmission between neurons, impairing the brain’s development and function. In this study, we sought to shed light on other, previously unknown mechanisms through which mutations in the SHANK3 gene disrupt brain development, leading to autism."
The team used a genetically engineered mouse model with a SHANK3 mutation mirroring that in humans with this type of autism. They focused on two brain components: non-neuronal brain cells (glia) called oligodendrocytes and the myelin they produce, which had not been heavily studied in this context.
They discovered the mutation causes a dual impairment in brain development and function, Fischer said.
“First, in oligodendrocytes, as in neurons, the SHANK3 protein is essential for binding and functioning of receptors that receive chemical signals,” she said. “This means the defective protein associated with autism disrupts message transmission to these vital support cells.”
Secondly, she explained, myelin production is disrupted when oligodendrocytes’ function and development are impaired.
“The faulty 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 brain regions,” she said. “In our model, we found myelin impairment in multiple brain areas, which affected the animals’ behavior."
The team explored a potential treatment and hopes to develop a therapy for humans. They took oligodendrocytes from a mouse with a SHANK3 mutation and inserted DNA containing the normal human SHANK3 sequence.
The goal
“Our goal was to allow the normal gene to encode a functional protein, which, replacing the defective protein, would restore its role in the cell,” Fischer said. “Following treatment, the cells expressed the normal SHANK3 protein, enabling functional receptor binding. The genetic treatment repaired the oligodendrocytes’ communication sites, essential for their proper development and function as myelin producers."
The study identified two new brain mechanisms involved in genetically induced autism: damage to oligodendrocytes and subsequent damage to the myelin they produce, Barak said.
“Recognizing the significance of myelin impairment in autism—whether linked to the SHANK3 gene or not—opens new pathways for understanding brain mechanisms underlying autism and for future treatments,” 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.