According to preliminary research, immune cells in the brain could be potential new drug targets for ASD and intellectual disability.
Researchers have discovered a convergent mechanism that may explain how two of the top genetic risk factors for autism spectrum disorder/intellectual disability (ASD/ID) lead to these neurodevelopmental disorders.
Scientists at the University of Buffalo have discovered a convergent mechanism that may explain how two of the top genetic risk factors for autism spectrum disorder/intellectual disability (ASD/ID) lead to these neurodevelopmental disorders.
While ASD is distinct from ID, a significant proportion of people with ASD (approximately 31 percent) also have ID. At the molecular level, neither condition is well understood.
"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 shared process at the molecular level between two different genes that could be underlying the behavioral changes," said Megan Conrow-Graham, PhD, first author and an MD/PhD candidate in UB's Jacobs School of Medicine and Biomedical Sciences.
The paper, which was published today in the journal Brain, focuses on ADNP and POGZ, the two top-ranked risk factor genes for ASD/ID. The study shows that mutations in these genes cause abnormal activation and overexpression of immune response genes as well as genes for a type of immune cell in the brain known as microglia.
"Our discovery opens the door to targeting microglia and immune genes for treatment of ASD/ID, but much more research is needed given the heterogeneity and complexity of these brain disorders," said Zhen Yan, PhD, senior author and SUNY Distinguished Professor in the Jacobs School's Department of Physiology and Biophysics.
Mutations in the two genes studied by the UB researchers activate microglia and cause immune genes in the brain to be overexpressed. The hypothesized outcome is abnormal synaptic function in the brain, which is a feature of ASD/ID.
The study included postmortem brain tissue from people with ASD/ID, as well as mouse studies in which ADNP and POGZ were silenced via viral delivery of small interference RNA. These mice performed poorly on cognitive tasks such as spatial memory, object recognition memory, and long-term memory.
A repressive function is being weakened.
"Under normal circumstances, cells in the central nervous system should not express large amounts of genes that activate the immune system," Conrow-Graham explained. "Both ADNP and POGZ work to repress these genes so that inflammatory pathways are not constantly activated, potentially causing damage to surrounding cells. When that repression is broken, these immune and inflammatory genes can be expressed in large numbers."
The pro-inflammatory response was activated in the mouse prefrontal cortex by upregulated genes caused by ADNP or POGZ deficiencies.
"This is consistent with what we've seen in upregulated genes in the prefrontal cortex of people with ASD/ID," Conrow-Graham said. The prefrontal cortex is the area of the brain that is in charge of executive functions like cognition and emotional control.
The mutated genes also activate microglia, which are glial cells in the brain that serve as support cells for neurons and have an immune function; they account for 10-15% of all brain cells.
Microglia with high sensitivity
"Microglia are extremely sensitive to pathological changes in the central nervous system, and they are the primary form of active immune defense to maintain brain health," Yan explained. "Abnormal activation of microglia, which we show occurs as a result of ADNP or POGZ deficiency, could lead to the damage and loss of synapses and neurons."
The researchers hope that future research will determine whether chronic neuroinflammation is directly contributing to at least some cases of ASD/ID, in which case targeting microglia or inflammatory signaling pathways could be beneficial.
The researchers noted that the clinical presentation of ASD and ID is extremely variable. Significant variation is also likely in the types of mechanisms responsible for ASD and/or ID symptoms.
"We discovered that changes in two risk genes result in a convergent mechanism, most likely involving immune activation," Conrow-Graham said. "However, this is unlikely to be true for all people with ASD/ID. When designing clinical trials to assess treatment efficacy, I believe our findings highlight the importance of taking into account the genetic factors involved in an individual's ASD/ID."
The study is the culmination of Conrow-PhD Graham's work; she has now returned to the Jacobs School to finish the last two years of her MD degree. Her experience pursuing both an MD and a PhD was described as extremely complementary.
The immune system plays a part.
"My training at each level was extremely beneficial in supplementing the other," she said. "I had completed two years of MD training when I started my PhD, so I was familiar with the fundamentals of physiology, anatomy, and pathology. As a result, I was able to broaden the scope of my neuroscience research, identifying how the immune system might be involved. Our lab had not previously investigated immunology-related pathways, so having that background knowledge was extremely beneficial."
She went on to say that she learned a lot from all of her colleagues in Yan's lab, including faculty, lab technicians, and other students. "Thanks to the dedication of lab coworkers for my training, I learned so many technical skills that I had never used before joining the lab," she said.
Her experience working on the basic science underlying neuropsychiatric disorders at the lab bench will undoubtedly influence her work as a clinician.
"I want to be a child and adolescent psychiatrist, so I might be able to work directly with this patient population," she said. "We are now learning that better care may be possible by using a personalized medicine approach that takes genetics, psychosocial factors, and other factors into account. It was a privilege to be able to delve deeply into the field of psychiatric genetics, which I hope will help me provide the best care for patients."
The Nancy Lurie Marks Family Foundation funded the study, as did a National Institutes of Health Ruth L. Kirschstein Individual Predoctoral NRSA for MD/Ph.D. F30 fellowship for Conrow-Graham.
Source: Materials provided by University at Buffalo.
Reference: DOI: 10.1093/brain/awac152