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Researchers at the University of Toronto have discovered a genetic network linked to autism. The results will facilitate the development of new therapies for this common neurological disorder.
As part of an autism-focused collaborative research program led by Benjamin Blencowe, Professor at the Donnelly Center for Cellular and Biomolecular Research at the University of Toronto, Thomas Gonatopoulos-Pournatzis , a postdoctoral fellow, has uncovered a network of more than 200 genes involved in the control of alternating splicing events often disrupted by Autism Spectrum Disorder (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 modification of cerebral cabling and behavior observed in autism.
Microexons
Better known for its effects on social behavior, it is thought that autism is caused by cerebral cerebral accidents.
"Our study revealed a mechanism underlying splicing of very short coding segments found in genes with genetic links to autism. This new knowledge provides a better understanding of how to target this mechanism for therapeutic applications, "says Blencowe, a professor in the Department of Molecular Genetics and the Banbury Chair in Medical Research at the University of Toronto (19659008). ] Hundreds of genes have been linked to autism, making its genetic basis difficult to unravel. The alternative splicing of small gene fragments, or microexons, appeared as a rare unifying concept in the molecular basis of autism after Blencowe's team had discovered that microexons were disrupted in a large proportion of autistic patients.
As a small gene encoding a protein segments, microexons have an impact on the ability of proteins to interact with one another during neuronal circuit formation. 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 coding segments, or exons, as a means of enhancing function. directories of protein variants in cells.
Screening with CRISPR
Although scientists are well aware of how exons, which contain about 150 DNA letters, are spliced, we still do not know how much smaller microexons – a mere 3-27 letters of DNA long – are used in nerve cells.
"The small size of the microexons" is a challenge for the splicing machine and it's been a headache for many years that these tiny exons are recognized and spliced "[19659008] says Blencowe.
To answer this question, Gonatopoulos-Pournatzis has developed a method of identifying genes involved in the splicing of microexons.
Using the powerful tool of King CRISPR gene editing with Mingkun Wu and Ulrich Braunschweig at Blencowe Laboratory and Jason Moffat's laboratory at Donnelly Center, Gonatopoulos-Pournatzis removed cultured brain cells from each of the 20,000 genes in the genome to determine which which are required for microexon splicing It has identified 233 genes whose various roles suggest that microexons are regulated by a vast array of cellular components.
"A very important benefit of this screen is that e we have been able to capture genes that affect the splicing of microexons both directly and indirectly and learn how various molecular pathways impact on this process, "
explains Blencowe.
nSR100 / SRRM4
Gonatopoulos-Pournatzis was able to find other factors working in close collaboration with a major regulator of microexon, a protein identified previously. called nSR100 / SRRM4, previously discovered in Blencowe's lab. In collaboration with the team of Anne-Claude Gingras of the Lunenfeld-Tanenbaum Research Institute of the Sinai Health System, they identified the Srsf11 and Rnps1 proteins as forming a molecular complex with nSR 100. [19659003] Knowledge of the precise molecular mechanisms of microexon splicing will help guide future efforts to develop potential therapies 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 splicing of microexons in a specific way. the brain. When you know the mechanism, you can potentially target it by using rational approaches to develop therapies against neurodevelopmental disorders, "
explains Gonatopoulos-Pournatzis.
Thomas Gonatopoulos-Pournatzis, Mingkun Wu, Ulrich Braunschweig, Jonathan Roth, Han Hong, Andrew J. Best, Raj Bushra, Michael Aregger, O Dave O. Hanlon, Jonathan D. Ellis, John A. Calarco, Jason Moffat , Anne-Claude Gingras and Benjamin J. Blencowe
Examination of the CRISPR-Cas9 fitting on the genome Networks reveals a mechanism of recognition of neuronal microexons disordered by autism
Molecular Cell Volume 72, Issue 3, p510 -524.E12, November 01, 2018Picture: Thomas Gonatopoulos-Pournatzis [19659027] [ad_2]
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