PhD student Inbar Fischer Credit Tel Aviv University
A groundbreaking study from Tel Aviv University enhances our understanding of the biological mechanisms behind genetically based autism. It mainly focuses on mutations in the SHANK3 gene, which are responsible for nearly one million autism cases worldwide. Based on these findings, the research team applied a genetic treatment that improved the functioning of cells affected by the mutation, paving the way for future therapies for SHANK3-related autism.
The study was led by the lab of Prof. Boaz Barak and PhD student Inbar Fischer from the Sagol School of Neuroscience and the School of Psychological Sciences at Tel Aviv University.
Prof. Barak: “Autism is a common neurodevelopmental disorder affecting 1-2% of the global population, with one in every 36 boys in the U.S. diagnosed. Its causes include environmental, genetic, and social factors, such as advancing parental age at conception. In my lab, we focus on the genetic causes of autism, particularly mutations in the SHANK3 gene. This gene is vital for the protein that binds receptors in neurons, essential for receiving chemical signals that enable neuron communication. Damage to SHANK3 can disrupt this communication, impairing brain development and function. Our study aims to explore previously unknown mechanisms through which SHANK3 mutations affect brain development, leading to autism.”
Specifically, the research team focused on two components in the brain that have not yet been studied extensively in this context: non-neuronal brain cells (glia) called oligodendrocytes and the myelin they produce. Myelin tissue is a fatty layer that insulates nerve fibres (axons), similar to the insulating layer that coats electrical cables. When the myelin is faulty, the electrical signals transmitted through the axons may leak, disrupting the message transmission between brain regions and impairing brain function.
The team employed a genetically engineered mouse model for autism, introducing a mutation in the Shank3 gene that mirrors the mutation found in humans with this form of autism. Inbar Fischer: “Through this model, we found that the mutation causes a dual impairment in the brain’s development and proper function: first, in oligodendrocytes, as in neurons, the SHANK3 protein is essential for the binding and functioning of receptors that receive chemical signals (neurotransmitters and others) from neighbouring cells. This means that the defective protein associated with autism disrupts message transmission to these vital support cells. Secondly, when the function and development of oligodendrocytes is impaired, their myelin production is also disrupted. 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 parts. In our model, we found myelin impairment in multiple brain areas and observed that the animals’ behaviour was adversely affected.”
The researchers then sought a method for fixing the damage caused by the mutation, hoping to develop a treatment for humans ultimately. Inbar Fischer: “We obtained oligodendrocytes from the brain of a mouse with a Shank3 mutation and inserted DNA segments containing the normal human SHANK3 sequence. Our goal was to allow the normal gene to encode a functional and normal protein, which would perform its essential role in the cell by replacing the defective protein. To our delight, following treatment, the cells expressed the normal SHANK3 protein, enabling the construction of a functional protein substrate to bind the receptors that receive electrical signals. In other words, the genetic treatment we had developed repaired the oligodendrocytes’ communication sites, essential for the cells’ proper development and function as myelin producers.”
To validate findings from the mouse model, the research team generated induced pluripotent stem cells from the skin cells of a girl with autism caused by a SHANK3 gene mutation identical to that in the mice. From these stem cells, they derived human oligodendrocytes with the same genetic profile. These oligodendrocytes displayed impairments similar to those observed in their mouse counterparts.
Prof. Barak concludes: “In our study, we discovered two new brain mechanisms involved in genetically induced autism: damage to oligodendrocytes and, consequently, damage to the myelin they produce. These findings have important implications – both clinical and scientific. Scientifically, we learned that defective myelin played a significant role in autism and identified the mechanism causing the damage to myelin. Additionally, we revealed a new role for the SHANK3 protein: building and maintaining a functional binding substrate for receptors critical for message reception in oligodendrocytes (not just in neurons). We discovered that contrary to the prevailing view, these cells play essential roles in their own right, far beyond the support they provide for neurons — often seen as the leading players in the brain. In the clinical sphere, we validated a gene therapy approach that led to significantly improved development and function of oligodendrocytes derived from the brains of mice modelling autism. This finding offers hope for developing genetic treatment for humans, which could enhance the myelin production process in the brain. Furthermore, recognizing the significance of myelin impairment in autism—whether linked to the SHANK3 gene or not—opens new pathways for understanding the brain mechanisms underlying autism and paves the way for future treatment development.