From The University at Buffalo-SUNY: “When autism spectrum disorder occurs with intellectual disability a convergent mechanism for two top-ranking risk genes may be the cause”

SUNY Buffalo

From The University at Buffalo-SUNY

June 30, 2022
Ellen Goldbaum

1
“When designing clinical trials to evaluate treatment effectiveness, I think our research underscores the importance of considering the genetic factors involved in an individual’s ASD/ID,” said Conrow-Graham. The paper published in Brain is the culmination of her PhD work in the Jacobs School of Medicine and Biomedical Sciences. (Photo: Sandra Kicman)

Preclinical study reveals that immune cells in the brain could be possible new drug targets for ASD and intellectual disability.

University at Buffalo scientists have discovered a convergent mechanism that may be responsible for how two top-ranked 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 — approximately 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 potential mechanisms contributing to the disorders, it is exciting to find a shared process between two different genes at the molecular level that could be underlying the behavioral changes,” said Megan Conrow-Graham, first author and an MD/PhD candidate in the Jacobs School of Medicine and Biomedical Sciences at UB.

Published today in the journal Brain, the paper focuses on ADNP and POGZ, the two top-ranked risk factor genes for ASD/ID. The research demonstrates 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 the possibility of targeting microglia and immune genes for treating ASD/ID, but much remains to be studied, given the heterogeneity and complexity of these brain disorders,” said Zhen Yan, PhD, senior author and SUNY Distinguished Professor in the Department of Physiology and Biophysics in the Jacobs School.

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

The research involved studies on postmortem brain tissue from humans with ASD/ID, as well as studies on mice in which ADNP and POGZ were silenced through viral delivery of small interference RNA. These mice exhibited impaired cognitive task performance, such as spatial memory, object recognition memory and long-term memory.

Weakening a repressive function

“Under normal conditions, cells in the central nervous system should not express large quantities of genes that activate the immune system,” said 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 are then able to be expressed in large quantities.”

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 humans with ASD/ID,” said Conrow-Graham. The prefrontal cortex is the part of the brain responsible for executive function, such as cognition and emotional control.

The mutated genes also activate the glial cells in the brain called microglia, which serve as support cells for neurons and have an 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,” explained Yan. “Aberrant activation of microglia, which we demonstrate occurs as a result of deficiency in ADNP or POGZ, could lead to the damage and loss of synapses and neurons.”

The researchers are hopeful that future research will determine whether chronic neuroinflammation could be directly contributing to at least some cases of ASD/ID, in which targeting microglia or inflammatory signaling pathways could prove to be a useful treatment.

The researchers pointed out that the clinical presentation of both ASD and ID is incredibly varied. Significant variation also likely is present in the kinds of mechanisms responsible for the symptoms of ASD and/or ID.

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

The research is the culmination of Conrow-Graham’s PhD work; she has now returned to complete the last two years of the MD degree in the Jacobs School. She described her experience pursuing both an MD and a PhD as extremely complementary.

The immune system has a role

“My training at each level was super helpful to supplement the other,” she said. “When I began my PhD, I had completed two years of MD training, so I was familiar with the basics of physiology, anatomy and pathology. Because of this, I was able to bring a broader perspective to my neuroscience research, identifying how the immune system might be playing a role. Prior to this, our lab had not really investigated immunology-related pathways, so having that background insight was really beneficial.”

She added that she learned so much from all of her colleagues in Yan’s lab, including faculty members, 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 co-workers for my training,” she said.

Her experience at the lab bench working on the basic science underlying neuropsychiatric disorders will definitely influence her 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,” she said. “We’re learning now that better care may be able to be provided by taking a personalized medicine approach, taking into account genetics, psychosocial factors and others. Being able to take a very deep dive 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 fellow; Ping Zhong, PhD, senior research scientist; Qing Cao, PhD, postdoctoral fellow; and Benjamin Rein, PhD, former graduate student.

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

See the full article here .

five-ways-keep-your-child-safe-school-shootings

Please help promote STEM in your local schools.

Stem Education Coalition

SUNY Buffalo Campus

The University at Buffalo-SUNY is a public research university with campuses in Buffalo and Amherst, New York, United States. The university was founded in 1846 as a private medical college and merged with the State University of New York system in 1962. It is one of four university centers in the system, in addition to The University at Albany-SUNY, The University at Binghampton-SUNY, and The University at Stony Brook-SUNY . As of fall 2020, the university enrolls 32,347 students in 13 colleges, making it the largest public university in the state of New York.

Since its founding by a group which included future United States President Millard Fillmore, the university has evolved from a small medical school to a large research university. Today, in addition to the College of Arts and Sciences, the university houses the largest state-operated medical school, dental school, education school, business school, engineering school, and pharmacy school, and is also home to SUNY’s only law school. The University at Binghampton has the largest enrollment, largest endowment, and most research funding among the universities in the SUNY system. The university offers bachelor’s degrees in over 100 areas of study, as well as 205 master’s degrees, 84 doctoral degrees, and 10 professional degrees. The University at Buffalo and The University of Virginia are the only colleges founded by United States Presidents.

The University at Buffalo is classified as an R1 University, meaning that it engages in a very high level of research activity. In 1989, UB was elected to The Association of American Universities, a selective group of major research universities in North America. University at Buffalo’s alumni and faculty have included five Nobel laureates, five Pulitzer Prize winners, one head of government, two astronauts, three billionaires, one Academy Award winner, one Emmy Award winner, and Fulbright Scholars.

The University at Buffalo intercollegiate athletic teams are the Bulls. They compete in Division I of the NCAA, and are members of the Mid-American Conference.

The University at Buffalo is organized into 13 academic schools and colleges.

The School of Architecture and Planning is the only combined architecture and urban planning school in the State University of New York system, offers the only accredited professional master’s degree in architecture, and is one of two SUNY schools that offer an accredited professional master’s degree in urban planning. In addition, the Buffalo School of Architecture and Planning also awards the original undergraduate four year pre-professional degrees in architecture and environmental design in the SUNY system. Other degree programs offered by the Buffalo School of Architecture and Planning include a research-oriented Master of Science in architecture with specializations in historic preservation/urban design, inclusive design, and computing and media technologies; a PhD in urban and regional planning; and, an advanced graduate certificate in historic preservation.

The College of Arts and Sciences was founded in 1915 and is the largest and most comprehensive academic unit at University at Buffalo with 29 degree-granting departments, 16 academic programs, and 23 centers and institutes across the humanities, arts, and sciences.

The School of Dental Medicine was founded in 1892 and offers accredited programs in DDS, oral surgery, and other oral sciences.

The Graduate School of Education was founded in 1931 and is one of the largest graduate schools at University at Buffalo. The school has four academic departments: counseling and educational psychology, educational leadership and policy, learning and instruction, and library and information science. In academic year 2008–2009, the Graduate School of Education awarded 472 master’s degrees and 52 doctoral degrees.

The School of Engineering and Applied Sciences was founded in 1946 and offers undergraduate and graduate degrees in six departments. It is the largest public school of engineering in the state of New York. University at Buffalo is the only public school in New York State to offer a degree in Aerospace Engineering.

The School of Law was founded in 1887 and is the only law school in the SUNY system. The school awarded 265 JD degrees in the 2009–2010 academic year.

The School of Management was founded in 1923 and offers AACSB-accredited undergraduate, MBA, and doctoral degrees.

The School of Medicine and Biomedical Sciences is the founding faculty of the University at Buffalo and began in 1846. It offers undergraduate and graduate degrees in the biomedical and biotechnical sciences as well as an MD program and residencies.

The School of Nursing was founded in 1936 and offers bachelors, masters, and doctoral degrees in nursing practice and patient care.

The School of Pharmacy and Pharmaceutical Sciences was founded in 1886, making it the second-oldest faculty at University at Buffalo and one of only two pharmacy schools in the SUNY system.

The School of Public Health and Health Professions was founded in 2003 from the merger of the Department of Social and Preventive Medicine and the University at Buffalo School of Health Related Professions. The school offers a bachelor’s degree in exercise science as well as professional, master’s and PhD degrees.

The School of Social Work offers graduate MSW and doctoral degrees in social work.

The Roswell Park Graduate Division is an affiliated academic unit within the Graduate School of UB, in partnership with Roswell Park Comprehensive Cancer Center, an independent NCI-designated Comprehensive Cancer Center. The Roswell Park Graduate Division offers five PhD programs and two MS programs in basic and translational biomedical research related to cancer. Roswell Park Comprehensive Cancer Center was founded in 1898 by Dr. Roswell Park and was the world’s first cancer research institute.

The University at Buffalo houses two New York State Centers of Excellence (out of the total 11): Center of Excellence in Bioinformatics and Life Sciences (CBLS) and Center of Excellence in Materials Informatics (CMI). Emphasis has been placed on developing a community of research scientists centered around an economic initiative to promote Buffalo and create the Center of Excellence for Bioinformatics and Life Sciences as well as other advanced biomedical and engineering disciplines.

Total research expenditures for the fiscal year of 2017 were $401 million, ranking 59th nationally.

SUNY’s administrative offices are in Albany, the state’s capital, with satellite offices in Manhattan and Washington, D.C.

With 25,000 acres of land, SUNY’s largest campus is The SUNY College of Environmental Science and Forestry, which neighbors the State University of New York Upstate Medical University – the largest employer in the SUNY system with over 10,959 employees. While the SUNY system doesn’t officially recognize a flagship university, the University at Buffalo and Stony Brook University are sometimes treated as unofficial flagships.

The State University of New York was established in 1948 by Governor Thomas E. Dewey, through legislative implementation of recommendations made by the Temporary Commission on the Need for a State University (1946–1948). The commission was chaired by Owen D. Young, who was at the time Chairman of General Electric. The system was greatly expanded during the administration of Governor Nelson A. Rockefeller, who took a personal interest in design and construction of new SUNY facilities across the state.

Apart from units of the unrelated City University of New York (CUNY), SUNY comprises all state-supported institutions of higher education.