A team of scientists fromUniversity of Buffalo revealed, in recent research, a convergent dynamic that may be responsible for how 2 high-level risk genes for the autism spectrum disorder/ intellectual disability (ASD / ID) lead to these neurodevelopmental disorders.
The results of the study have been published in the scientific journal Brain.
2-gene mutation and autism spectrum disorder / intellectual disability: here’s what the new research has revealed
Although ASD is distinct from ID, a significant percentage, around 31%, of people with ASD also show ID. Neither condition is well understood at the molecular level.
“Given the vast number of genes known to be involved in ASD / ID and the many potential mechanisms contributing to the disorders, it is exciting to find a process shared between 2 different genes at the molecular level that could underlie the behavioral changes.“, he has declared Megan Conrow-Grahamfirst author researcher at the Jacobs School of Medicine and Biomedical Sciences at UB.
The study was based on the study of ADNP And POGZ, the 2 most important risk factor genes for ASD / ID. Research shows that mutations in these genes result in abnormal activation and overexpression of immune response genes and genes for a type of immune cell in the brain called microglia.
“Our discovery opens up the possibility of targeting microglia and immune genes for the treatment of ASD / ID, but much remains to be studied given the heterogeneity and complexity of these brain disorders.“, he has declared Zhen Yan, senior author e SUNY Distinguished Professor in the Department of Physiology and Biophysics of the Jacobs School.
UB scientists revealed that mutations in the 2 genes studied activate microglia and cause immune genes to over-express in the brain. The hypothesized result is the abnormal function of synapses in the brain, a feature of ASD / ID.
The research involved post mortem brain tissue analyzes of humans with ASD / ID, as well as studies in mice in which ADNP and POGZ were silenced through viral delivery of a small interfering RNA.. These mice exhibited impaired cognitive performance, such as spatial memory, object recognition memory, and long-term memory.
“Under normal conditions, central nervous system cells should not express large amounts of genes that activate the immune system“, Explained Conrow-Graham:”ADNP and POGZ both work to repress these genes so that inflammatory pathways are not continuously activated, which could damage surrounding cells. When that repression is weakened, these immune and inflammatory genes can then be expressed in large quantities ”.
The 2 upregulated genes in the deu topu prefrontal cortex caused by ADNP or POGZ deficiencies triggered the pro-inflammatory response: “This is consistent with what we see in upregulated genes in the prefrontal cortex of humans with ASD / ID, “continued Conrow-Graham:” The prefrontal cortex is the part of the brain responsible for executive functions, such as cognition and emotional control.“.
The 2 mutated genes also activate glial cells in the brain called microglia, which act as support cells for neurons and have an immune function in the brain: they comprise 10-15% of all brain cells: “Microglia are very sensitive to pathological changes in the central nervous system and are the main form of active immune defense to maintain brain health“Explained Yan: “Aberrant activation of microglia, which we demonstrate occurs due to ADNP or POGZ deficiency, could lead to damage and loss of synapses and neurons.”
Researchers believe future studies will determine whether chronic neuroinflammation could directly contribute to at least some cases of ASD / ID, in which targeting microglia or inflammatory signaling pathways could prove to be a useful treatment. Scientists also found that the clinical presentation of both ASD and ID is incredibly diverse. Significant variation is also likely to be present in the types of mechanisms responsible for ASD and / or ID symptoms.
“We found that changes in 2 risk gebi lead to a convergent mechanism, probably involving immune activation“, Conrow-Graham added:“However, this is probably not the case for all individuals with ASD / ID. When designing clinical trials to evaluate treatment efficacy, I think our research underscores the importance of considering the genetic factors involved in an individual’s ASD / ID. “
“My training at every level has been of great help in integrating the other “, Conrow-Graham said: “When I started my PhD, I had completed two years of medical training, so I was familiar with the basics of physiology, anatomy and pathology. For this reason, I was able to bring a broader perspective to my neuroscientific research, to identify how the immune system might play a role. Before that, our lab hadn’t really studied immunology-related pathways, so having that basic insight was really helpful. “
The scientist added that she learned so much from all of her colleagues in Yan’s lab, including faculty, lab technicians, and other students: “I learned so many technical skills that I had never used before entering the lab, thanks to the dedication of my lab colleagues for my training.“. His experience at the laboratory working on the basic science behind neuropsychiatric disorders will certainly influence his work as a clinician.
“I plan to pursue a career as a child and adolescent psychiatrist so I may be able to work directly with this patient population“, he said. “We are learning now that better care can be provided by adopting a personalized medicine approach, taking into account genetics, psychosocial and other factors. Being able to take a very deep dive into the field of psychiatric genetics has been a privilege that I hope will help me provide the best patient care“, He concluded.
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