The California Institute for Regenerative Medicine (CIRM) is supporting innovative research into neuro diseases, including a project examining how air pollution may contribute to autism.
Through the Research using Multidisciplinary, Innovative approaches in Neuro Diseases (ReMIND) program, Stuart Lipton, MD, PhD, and co-investigators Tomo Nakamura, PhD, John Yates, PhD, Marisa Roberto, PhD, and Nik Schork, PhD, are studying how pollutants such as PM2.5 and nitrogen oxides may drive autism spectrum disorder (ASD) and intellectual disability (ID). Their work focuses on how these pollutants trigger redox stress and alter protein function through chemical changes like S-nitrosylation. Using advanced multiomics techniques, including redox proteomics, the team aims to identify treatable targets and develop new therapies for ASD and ID.
Dr. Lipton sat down to discuss the team’s research. Some responses have been edited for clarity and brevity.
Please share a summary of your research project. Is there a particular disease focus? Is there a broader question that this project is hoping to address?
Dr. Lipton: ASD and ID are highly prevalent. In the United States, ASD affects an estimated one in every 36 births. Aside from symptomatic treatments, no definitive therapies exist. Most cases of ASD and ID are not tied to rare genetic mutations, and their causes remain unclear. Identifying those causes and the underlying mechanisms could open the door to new treatments.
Research shows that ASD and ID arise from multiple factors, including interactions between genetic and environmental risks. Recent studies point to air pollution as a major environmental contributor, increasing the risk of both conditions. Emerging evidence also shows that air pollutants trigger redox stress, activating harmful signaling pathways that may contribute to ASD and ID.
With support from the CIRM award, we are investigating how these processes occur. Our goal is to identify treatable targets related to pollutant‑driven ASD and ID using a multidisciplinary strategy. This work will guide the development of new therapeutic drugs.
Our approach examines how air pollution influences ASD and ID through multiomics, with redox proteomics at the core. We focus on chemical reactions such as protein S-nitrosylation, which our group first identified in biological samples.
Although several reactions involve NOx, S-nitrosylation is the dominant effect on proteins. It adds nitrogen and oxygen to a cysteine residue, altering protein function and causing dysfunction in disease. Our group pioneered the discovery of these reactions and developed methods to detect them in the human brain and in hiPSC‑derived brain organoids. Using modern mass spectrometry and specialized probes such as SNOTRAP, we can precisely identify these modifications.
Based on our findings in Alzheimer’s and Parkinson’s disease, we expect to identify roughly 2,000 abnormally S‑nitrosylated proteins in ASD. Many of these proteins are likely to play key roles in the condition’s development.
Why is research on neuropsychiatric disorders and diseases affecting the central nervous system (CNS) so important?
Dr. Lipton: Neuropsychiatric diseases such as ASD/ID are among the most debilitating afflictions of human society, and their incidence is rapidly growing. We have identified a new cause related to climate change-induced air pollution contributing to the development of ASD/ID. Our newly identified chemical mechanism, involving contaminants in air pollution that affect protein structure in the human brain, offers hope for new treatments to be developed.
The ReMIND program is a pilot for collaborative, multi-investigator funding for foundational basic discovery research. Could you speak to the timeliness and impact of such funding structures more broadly and why you think such funding structures will be impactful for CIRM’s mission?
Dr. Lipton: Research over the last 25 years has evolved into multidisciplinary approaches by teams of scientists versed in various aspects of science, ranging from molecular genetics to protein structure and stem cells. The ReMIND program allows for teams of scientists to work together to take on brain diseases with this unique approach, fostering individuals performing experiments as well as the group in aggregate evaluating and moving forward with the project using the most current techniques.
Can you describe CIRM’s impact over the last 20 years?
Dr. Lipton: In my view, CIRM is now on the cusp of providing novel therapies base on the use of human stem cell to either develop new drugs or cell-based treatments for previously untreatable diseases.
The last frontier in this regard is the brain. With the new ReMIND-L program, CIRM is forging into this last frontier in order to better the lives of Californians and others throughout the world.
Learn more about the ReMIND program at cirm.ca.gov/remind.
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