Summary: Autism-linked SHANK3 gene mutations undermine not merely neurons but furthermore oligodendrocytes, necessary for producing nerve, which insulates muscle fibers. This impairment affects behaviour and reduces the effectiveness of mental signals.
Using gene therapy, experts successfully repaired these tissues in a rat design, restoring their work and nerve production. They validated their studies with human-derived plant organisms, confirming related deficits and maintenance methods.
This finding opens the door to novel therapies for nerve function and highlights a significant role that oligodendrocytes play in autism. The research highlights both the potential for treatment and the natural difficulty of autism.
Important Information:
- SHANK3 mutations affect nerve creation, disrupting neural sign efficiency.
- In animals and people cells, gene therapy restored right work to chondrocytes.
- Findings identify the crucial role of oligodendrocytes in autism beyond cerebral support.
Origin: Tel Aviv University
A pioneering research from Tel Aviv University expands the knowledge of the natural process underlying genetically-based autism, especially mutations in the , SHANK3 , protein, responsible for nearly one million cases of dementia worldwide.
Based on these insights, the research team applied a biological treatment that improved the performance of cells affected by the gene, laying a foundation for future solutions for , SHANK3-related dementia.
In partnership with Prof. Ben Maoz from the Fleischman Faculty of Engineering at Tel Aviv University, Prof. Shani Stern from the University of Haifa, and Prof. Boaz Barak’s test, both of whom led the study, led the study.
The article was published in the exclusive journal , Science Advances.
Prof. Barak:” Autism is a fairly common developmental disorder. One in every 36 boys in the U.S. and 1-2 % of the world’s population are diagnosed with autism spectrum disorder ( ASD ), with numbers increasing over time.
” Autism is caused by a wide range of aspects – environmental, hereditary, and even social and cultural ( such as the increase in familial time at conception ).
” In my laboratory, we study biological causes of dementia. Among these, variants in a protein called , SHANK3.
We are well-versed in the effects of these mutations on brain neurons ‘ functions, and we are aware of this fact because the protein, SHANK3 , is crucial for binding neuronal receptors, which are required for receiving chemical signals ( neurotransmitters and other ) by which neurons communicate.
” Thus, injury to this gene may destroy information transmission between neurons, impairing the mind’s development and function.
” In this research we sought to shed light on another, recently mysterious mechanisms, through which mutations in the , SHANK3 , protein undermine brain development, leading to disorders manifested as autism.”
Specifically, the research team focused on two components in the brain not yet studied extensively in this context: non-neuronal brain cells ( glia ) called oligodendrocytes and the myelin they produce.
Similar to the insulating layer that covers electrical cables, myelin tissue is a fatty layer that protects nerve fibers ( axons ). The electric signals sent through the axons may leak, causing a loss of communication between brain regions and compromising brain function when the myelin is defective.
The group employed a genetically engineered rat model for dementia, introducing a gene in the , Shank3 , protein that mirrors the gene 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 neighboring cells.
This implies that these crucial support cells are hampered by the defective proteins linked to autism. Firstly, when the performance and development of chondrocytes is impaired, their axons manufacturing is also disrupted.
The photoreceptor axons are not adequately insulateled by the malfunctioning myelin, which results in less effective electrical signal transfer between brain cells as well as synchronized electrical activity between various brain regions.
Our model revealed myelin deficits in various brain regions, and we found that this led to the creatures ‘ conduct being harmed.
The researchers then sought a way to repair the mutation’s damage, with the goal of eventually developing a human care.
Inbar Fischer:” We obtained chondrocytes from the head of a keyboard with a , Shank3 , gene, and inserted Genome segments containing the ordinary human , SHANK3 , series.
Our goal was to replace the defective protein with a functional and normal protein that would play a key role in the cell. 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 developed restored the communication points between oligodendrocytes, which are necessary for the cells ‘ proper development and function as myelin producers.
The research team extracted induced pluripotent stem cells from a girl with autism who had a , SHANK3 , a gene mutation that was identical to the mouse model in order to validate findings from the mouse model.
Human oligodendrocytes with the same genetic profile were created from these stem cells. Similar impairments to those seen in their mouse counterparts were present in these oligodendrocytes.
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 significant clinical and scientific implications.  , Scientifically, we learned that defective myelin plays 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 ). Contrary to popular belief, these cells, in fact, play fundamental roles in their own right, far beyond the support they provide neurons, who are frequently regarded as the main players in the brain.
We demonstrated a gene therapy strategy that significantly improved the development and function of oligodendrocytes from mice modeling autism in the clinical setting.
” This finding provides a hopeful prospect for human genetic therapy that could enhance the brain’s myelin production process.
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”.
About this news article on autism and genetics
Author: Noga Shahar
Source: Tel Aviv University
Contact: Noga Shahar – Tel Aviv University
Image: The image is credited to Neuroscience News
Original Research: Open access.
Boaz Barak and colleagues ‘ study,” Shank3 mutation impairs glutamate signaling and myelination in human iPSC-derived OPCs.” Science Advances
Abstract
In ASD mouse models and human iPSC-derived OPCs, the Shank3 mutation impairs glutamate signaling and myelination.
Autism spectrum disorder ( ASD ) is characterized by social and neurocognitive impairments, with mutations of the , SHANK3 , gene being prominent in patients with monogenic ASD.
Using the InsG3680 mouse model with a , Shank3 , mutation seen in humans, we revealed an unknown role for Shank3 in postsynaptic oligodendrocyte ( OL ) features, similar to its role in neurons. The primary OL cultures derived from InsG3680’s exhibit impaired molecular and physiological glutamatergic behaviors.
In vivo, InsG3680 mice exhibit significant reductions in the expression of key myelination–related transcripts and proteins, along with deficits in myelin ultrastructure, white matter, axonal conductivity, and motor skills. Last, we observed significant impairments, with clinical relevance, in induced pluripotent stem cell–derived OLs from a patient with the InsG3680 mutation.
Our study combined uncovers a mechanism for the crucial link between myelination and ASD pathology and provides insight into Shank3’s role in OLs.
