When ASD occurs with intellectual disability, a convergent mechanism for two highest-ranking risk genes may be the cause

BUFFALO, NY – Scientists at the University of Buffalo have discovered a convergent mechanism that may account for how two highly regarded genetic risk factors for autism spectrum disorder/intellectual disability (ASD/ID) lead to these neurodevelopmental disorders.

Although ASD is different from ID, a significant proportion – about 31% – of people with ASD also exhibit 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 possible mechanisms contributing to the disorders, it is exciting to find a shared process between two different genes at the molecular level that could underlie the could be due to the behavioral changes,” said Megan Conrow-Graham, PhD, lead author and an MD/PhD candidate in the Jacobs School of Medicine and Biomedical Sciences at UB.

Published today in Brain magazine, the paper focuses on ADNP and POGZ, the two best-ranked risk factor genes for ASD/ID. The 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 finding 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,” said Zhen Yan, PhD, senior author at SUNY Distinguished Professor in the Department of Physiology and Biophysics in the Jacobs School.

The UB scientists discovered that mutations in the two genes studied activate microglia and cause immune genes to be overexpressed in the brain. The hypothesized result is the abnormal function of synapses in the brain, a hallmark of ASD/ID.

The research included studies on postmortem brain tissue from people with ASD/ID, as well as studies in mice in which ADNP and POGZ were silenced by viral release of small interfering RNA. These mice showed impaired cognitive task performance, such as spatial memory, object recognition memory, and long-term memory.

Weaken a repressive function

“Under normal circumstances, cells in the central nervous system should not be expressing large amounts of genes that activate the immune system,” Conrow-Graham said. “ADNP and POGZ both work to suppress 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 high amounts.”

The upregulated genes in the mouse prefrontal cortex caused by the deficiencies in ADNP or POGZ activated the pro-inflammatory response.

“This is consistent with what we see in upregulated genes in the prefrontal cortex of people with ASD/ID,” Conrow-Graham said. The prefrontal cortex is the part of the brain responsible for executive functions, such as cognition and emotional control.

The mutated genes also activate glial cells in the brain called microglia, which serve as support cells for neurons and have immune function in the brain; they comprise 10-15% of all brain cells.

Sensitive microglia

“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,” explains Yan. “Aberrant activation of microglia, which we show to occur as a result of ADNP or POGZ deficiency, can lead to damage and loss of synapses and neurons.”

The researchers hope that future research will show whether chronic neuroinflammation could directly contribute to at least some cases of ASD/ID, where targeting microglia or inflammatory signaling pathways could prove a useful treatment.

The researchers pointed out that the clinical presentation of both ASD and ID is incredibly varied. There is also likely to be significant variation in the types of mechanisms responsible for the symptoms of ASD and/or ID.

“We found that changes in two risk genes lead to a convergent mechanism, probably with immune activation,” Conrow-Graham said. “However, this is probably not true for all individuals with ASD/ID. When designing clinical trials to evaluate the effectiveness of treatments, I think our research underscores the importance of considering the genetic factors involved in a person’s ASD/ID.”

The research is the culmination of Conrow-Graham’s PhD work; she is now back to complete the final two years of the MD degree at Jacobs School. She described her experience earning both an MD and a PhD as highly complementary.

The immune system has a role

“My training at each level was super helpful to complement the other,” she said. “When I started my PhD, I had completed two years of MD training, so I was familiar with the basics of physiology, anatomy and pathology. This allowed me to bring a broader perspective to my neuroscience research and identify how the immune system might play a role. Before that, our lab hadn’t really explored immunology-related pathways, so having that background insight was really helpful.”

She added that she learned so much from all her colleagues in Yan’s lab, including teachers, lab technicians and other students. “I learned so many technical skills that I had never used before joining the lab, thanks to the dedication of lab staff to my training,” she said.

Her experience on the lab bench working on the basic science underlying neuropsychiatric disorders is sure to influence her work as a clinician.

“I plan to pursue a career as a child and adolescent psychiatrist so that I may be able to work directly with this patient population,” she said. “We are now learning that better care can be provided by taking a personalized approach to medicine, taking into account genetics, psychosocial factors, and others. Being able to dive very deeply into the field of psychiatric genetics was a privilege that I hope will help me to provide the best care for patients.”

The research was funded by the Nancy Lurie Marks Family Foundation and by a National Institutes of Health Ruth L. Kirschstein Individual Predoctoral NRSA for MD/PhD F30 fellowship for Conrow-Graham.

In addition to Conrow-Graham and Yan, co-authors are Jamal B. Williams, PhD, former graduate student; Jennifer Martin, PhD, former postdoctoral researcher; Ping Zhong, PhD, senior researcher; Qing Cao, PhD, postdoctoral researcher; and Benjamin Rein, PhD, former graduate student.

All are current or former members of Yan’s lab.

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