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Researchers at the Donnelly Center have discovered a genetic network linked to autism. The results, described in the newspaper Molecular cell, will facilitate the development of new therapies for this common neurological disorder.
As part of a collaborative autism research program led by Benjamin Blencowe, Professor at the Donnelly Center for Cellular and Biomolecular Research at the University of Toronto, Thomas Gonatopoulos-Pournatzis Postdoctoral Fellow, lead author of the study, has uncovered a network of more than 200 genes involved in the control of alternative splicing events often disrupted in autism spectrum disorders (ASD). Alternative splicing is a process that functionally diversifies protein molecules – the building blocks of cells – in the brain and other parts of the body. The Blencowe laboratory had previously shown that the disruption of this process was closely related to the alteration of cerebral wiring and behavior in autism.
"Our study revealed a mechanism underlying splicing of very short coding segments present in genes with genetic links to autism," said Blencowe, a professor in the Department of Molecular Genetics and Holder. the Banbury Medical Research Chair at Columbia University. T.
"This new knowledge allows us to better understand the possible ways to target this mechanism for therapeutic applications".
Better known for its effects on social behavior, it is thought that autism is caused by cerebral cabling problems established during embryo development. Hundreds of genes have been linked to autism, making its genetic bases difficult to unravel. The alternative splicing of small gene fragments, or microexons, became a rare unifying concept in the molecular basis of autism after Blencowe's team had discovered that microexons were disrupted in a large population. proportion of autistic patients.
Learn how microexons contribute to autism
As tiny segments of genes encoding proteins, microexons have an impact on the ability of proteins to interact with one another when forming neural circuits. Microexons are particularly critical in the brain, where they are included in the RNA template for protein synthesis during the splicing process. Splicing allows the use of different combinations of protein-encoding segments, or exons, as a means of enhancing the functional repertoires of protein variants in cells.
And, although scientists are well aware of how the exons, which contain about 150 DNA letters, are spliced, it has not been determined how the much smaller micro-exons – 3 to 27 letters of DNA – are used in nerve cells.
"The small size of the microexons" presents a challenge for splicing machines and the way these tiny exons are recognized and spliced is a headache for many years, "said Blencowe.
To answer this question, Gonatopoulos-Pournatzis has developed a method of identifying genes involved in the splicing of microexons. Using the powerful CRISPR gene editing tool and collaborating with Mingkun Wu and Ulrich Braunschweig in the Blencowe lab as well as with Jason Moffat's lab at the Donnelly Center, Gonatopoulos-Pournatz took out brain cells grown each of the 20,000 genes of the gene to be found. which ones are needed for microexon splicing. He identified 233 genes whose various roles suggest that microexons are regulated by a vast network of cellular components.
"This screen has a very important advantage: we have been able to capture genes that affect the splicing of microexons, directly and indirectly, and we have learned how various molecular pathways affect this process," says Blencowe.
In addition, Gonatopoulos-Pournatzis was able to find other factors working in close collaboration with a previously identified microexon splice regulator, a protein called nSR100 / SRRM4, previously discovered in Blencowe's laboratory. In collaboration with the team of Anne-Claude Gingras of the Lunenfeld-Tanenbaum Research Institute of Sinai Health System, they identified proteins named Srsf11 and Rnps1 as forming a molecular complex with nSR100.
Knowing the precise molecular mechanisms of microexon splicing will help guide future efforts to develop a therapeutic potential for autism and other disorders. For example, since the splicing of microexons is disrupted in autism, researchers could look for drugs that can restore their levels to those seen in unaffected individuals.
"We now understand better the mechanism of recognition and specific splicing of microexons in the brain," said Gonatopoulos-Pournatzis, who recently won the Donnelly Center's Research Excellence Award. "When you know the mechanism, you can potentially target it by using rational approaches to develop therapies for neurodevelopmental disorders."
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