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The causes of Autism Spectrum Disorder (ASD) are diverse and, to some extent, unknown. But without a doubt, they are complex, layered and deeply nuanced. In a study published on January 17, 2019 in Translational psychiatry, researchers at the San Diego School of Medicine at the University of California at San Diego, describe how, in a new mouse model, epigenetic regulation has a negative impact on a downstream gene specifically involved in neurodevelopment and neurodegeneration. badociated behaviors.
"We had only clinical and genetic evidence of the correlation between the gene and autism." Now, with this mouse model, we have direct evidence establishing a causal link between this gene and alterations. neuronal and molecular leading to ASD-like behavior, "said lead author Alysson R Muotri, PhD, professor in the Departments of Pediatrics and Cellular and Molecular Medicine of the Faculty of Medicine at the University of San Diego, Director of the UC San Diego stem cell program and member of the Sanford Consortium for Regenerative Medicine.
"This animal model could be useful for testing potential therapeutic alternatives for this subgroup of human ASD Our plans also include the development of organoids from the human brain derived from reprogrammed cells from TSA subjects. "
Epigenetics refers to changes in organisms caused by the alteration of gene expression rather than by the alteration of the genetic code itself. Epigenetic control of chromatin structure – the way DNA is efficiently encapsulated in the nucleus of a cell – is involved in many critical cellular processes, from gene expression to division. cellular and neural development.
"The importance of epigenetic regulation mechanisms is increasingly recognized in human neurodevelopment and neurodevelopmental conditions, such as ASD," Muotri said. "Indeed, mutations in chromatin-related epigenetic genes can cause several neurological disorders."
Muotri and his colleagues specifically examined a group of proteins called SET domain, which writes an instructional code for methylation of histone, a process of adding or subtracting proteins to increase or decrease gene transcription. It is essential for the regulation of gene expression and the ability of different cells to express different genes.
SET-domain proteins are involved in a gene called SETD5, which is essential for neurodevelopment and has been clbadified in genetic studies as a gene with a high risk of ASD ", but it did not exist until then. now no cause-and-effect relationship between loss of function of SETD5 and changes in neurodevelopment. ", said Muotri.
In a murine model with a haplic deficiency of SETD5 (a single functional copy of the gene), the researchers found that cortical neurons had morphological alterations and reduced connectivity. "As a result, neural networks have shown developmental delay in these mice compared to controls," said Muotri.
The researchers then determined which genes were affected, identifying the neurodevelopmental pathways targeted by the SETD5 gene. They hypothesized that the expression of the affected gene would likely result in behavioral change and, in fact, abnormal patterns of social interaction and "autism-compatible" behavior at home. the mouse.
Magnetic resonance imaging revealed subtle anatomical differences in the mutant adult brain of affected mice. A more detailed anatomical study revealed an aberrant cortical stratification – a phenotype observed in other models of ASD mice.
The Muotri lab has developed a vast collection of cells carrying genes not at risk for ASD generated by the Tooth Fairy project.
Co-authors include: Spencer M. Moore, Jason S. Seidman, Richard Gao, Alex Savchenko, Ty D. Troutman, Yohei Abe, Josh Stender, Sicong Wang and Christopher K. Glbad, UC San Diego; Jacob Ellegood, Hospital for Sick Children, Toronto, CA; Daehoon Lee and Hoonkyo Suh, Cleveland Clinic; Bradley Voytek, UC San Diego and Kavli Institute for Brain and Mind; and Jason P. Lerch, Hospital for Sick Children and University of Toronto.
Disclosure: Alysson Muotri is a co-founder and holds a stake in TISMOO, a company dedicated to genetic badysis that focuses on therapeutic applications adapted to autism spectrum disorders and other neurological disorders of the origin genetic. The terms of this agreement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policy.
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