How Mutation in One Gene, RXRa, Impacts the Brain of Children with PANDAS/PANS
*This research is preliminary as projected to be submitted for publication in 2025
Ugur Akcan, a postdoctoral research scientist in the Agalliu Lab at Columbia University has investigated the effects of a genetic mutation identified in some children with PANDAS and PANS. This mutation affects the Retinoid X Receptor Alpha (RXRa) gene, a transcription factor that binds to genomic DNA and affects the expression of other genes and plays a crucial role in regulating the brain’s immune cells. These immune cells help protect the brain from infections and maintain its overall health.
How Was the RXRa Gene Mutation Discovered?
The mutation was identified through whole-exome sequencing of 84 children with PANDAS/PANS. It was present in a small subset of this group. This mutation is not typically screened for in standard genetic tests and is not considered the sole gene responsible for immune challenges in PANDAS/PANS. However, it represents one pathway connecting both immune and neuronal dysfunction since the gene is also present in neurons.
How Does RXRa Affect Microglia and the Immune Response?
To understand the impact of the RXRa gene, researchers conducted experiments using a mouse model for PANDAS. These mice were repeatedly exposed to Group A Streptococcus via the intranasal route, and the RXRa gene was “eliminated” specifically in microglia (the brain’s innate immune cells).
- Microglia’s Role in Immunity: Microglia are the brain’s innate immune cells that support neurons and act as the brain’s primary immune defense. When the RXRa gene was removed, microglia showed a decreased inflammatory response, which is typically needed to fight infections and recruit other immune cells to the site of infection.
- Impact on the Blood-Brain Barrier (BBB): The absence of RXRa disrupted the microglia’s ability to respond to bacterial infections. This led to increased activity of genes linked to antigen presentation, interferon response, and inflammation in endothelial cells (which form the BBB). As a result, the BBB lost its integrity, allowing harmful blood proteins to penetrate the brain. Tight junctions and transcytosis mechanisms, which are essential for BBB function, were impaired leading to BBB breakdown.
In summary, the RXRa mutation reduced microglial inflammation and caused damage to the BBB, making the brain more vulnerable to harmful substances. This highlights how a dysfunctional RXRa gene can significantly contribute to PANDAS/PANS.
Key Takeaways from the RXRa Gene Findings
This research provides important insights into how the immune system and inflammation affect brain function, particularly in children with PANDAS/PANS. It underscores the importance of studying the neuroimmune axis, which connects the immune system and the brain, as a vital area of biomedical research.
The findings challenge the traditional focus on neurons alone in psychiatric disorders. Instead, they emphasize the role of other central nervous system (CNS) cells, particularly those governing immune functions, in the development of neuropsychiatric symptoms after infections.
Moreover, the study highlights that microglia, the brain’s immune protectors, are crucial players in the development of behavioral abnormalities seen in post-infectious OCD. This research also points to genetic risk factors like RXRa mutations as potential contributors to psychiatric disorders, including OCD.
Biography of Dr. Ugur Akcan:
Dr. Uğur Akcan is a Postdoctoral Research Fellow at Columbia University, specializing in Neuroscience. His primary research interests lie in Neuropsychiatry, the Blood-Brain Barrier (BBB), and the intricate ways the immune system interacts with the BBB, particularly in the context of neuropsychological disorders.
During his Master’s studies, Dr. Akcan investigated immune mechanisms in Bipolar Disorder, exploring how these pathways are altered in affected patients. He deepened his expertise during his PhD, focusing extensively on the Blood-Brain Barrier and its role in various neurological conditions.
Currently, Dr. Akcan is leveraging his scientific knowledge to investigate the dynamic relationship between the immune system and the BBB in neuropsychological disorders, with a specific focus on PANDAS/PANS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections).
In 2022, Dr. Akcan was awarded a grant from the PANDAS Network and the International OCD Foundation (IOCDF) to support this groundbreaking project on an RXRa animal model of disease. His research now centers on creating a human 3D BBB model, which he uses to study how PANDAS/PANS patients respond to infections. Additionally, he has received a fellowship to further advance this innovative work.
Funding support is essential to advance Dr. Akcan’s groundbreaking project, which seeks to uncover the cellular mechanisms underlying the development of PANDAS/PANS. This research has the potential to revolutionize our understanding of these complex disorders and pave the way for innovative therapeutic approaches, ultimately improving the lives of affected children and their families. Your contribution could be a critical step in making these discoveries a reality.
