Brain cell activity plays a key role in the outcomes of CNS disorders

Cedars-Sinai researchers have comprehensively mapped the molecular activity in the brain and spinal cord that is responsible for regulating the body’s response to central nervous system (CNS) disorders, such as Alzheimer’s disease, Huntington’s disease, and spinal cord injuries.

The research focused on cellular changes in astrocytes, a type of specialized support cell in the brain and spinal cord. These cellular changes, collectively known as “reactivity,” play a crucial role in regulating the outcomes of central nervous system disorders.

This is the first time a team of scientists has provided evidence that astrocytes use specialized collections of molecules called transcriptional regulators to shape disorder-specific changes in their molecular profiles.

Discoverydescribed in detail in a peer-reviewed journal Naturecan help lead to the development of a wide range of new therapies that target specific astrocyte activity and help treat a variety of central nervous system conditions, including multiple sclerosis and stroke.

“There is a growing interest in targeting astrocyte reactivity as a treatment strategy for CNS disorders,” said Joshua Burda, PhD, lead author and co-correspondent of the study and assistant professor at the Department of Biomedical Sciences and the Department of Neurology. “Understanding how the different types of astrocyte responses are coordinated and the consequences of manipulating those responses will not only help us better understand central nervous system diseases, but can provide essential insights that will enable the development of better therapies for these conditions.”

Astrocyte reactivity is a hallmark of virtually all injuries and diseases of the nervous system. Yet there is still little understanding of what astrocyte reactivity is, what causes it, how it differs between disorders, and how these differences are regulated.

The term “reactivity” describes a remarkable variety of astrocyte cell transformations, each of which involves changes in gene expression. To find out more about the mechanisms that control these changes in astrocyte gene expression, Burda and his team first developed a bioinformatics tool to identify “regulators of astrocyte reactivity” – specialized molecules that determine gene expression – in various neurological injuries or diseases.

The method is based on a consensus of different types of data, including computational and biological experimental data, all of which must be reconciled in order for these specialized molecules to be positively identified.

Furthermore, the researchers used genetic analysis to verify reactivity of transcriptional regulators as a major determinant of CNS disorder progression and outcomes.

Together, the results of these studies have shown that controlling changes in gene expression reactivity is highly complex. The research team also showed for the first time how a relatively limited group of transcriptional regulators can interact and coordinate the altered expression of hundreds or even thousands of reactivity genes in astrocytes.

“With this broad body of data, we can now begin to investigate and link these modular regulatory pathways of the astrocyte gene to specific aspects and states of reactivity associated with numerous common neurological disorders,” Burda said. “Finally, we would like to use this information to therapeutically enhance adaptive responses while reducing the maladaptive aspects of astrocyte reactivity.” I also hope that our findings will prompt an important shift in the way people think about and study astrocyte reactivity. ”

Another co-author of the study is Michael Sofroniew, MD, PhD, a prominent professor in the Department of Neurobiology at UCLA. Other Cedars-Sinai authors include Burda Lab team members Keshav Suresh, a PhD candidate in the Cedars-Sinai Biomedical Sciences Program, and Sarah McCallum, PhD, a postdoctoral fellow.

Funding: The research mentioned in this publication was supported by grants from the National Institutes of Health (NS084039, F32NS096858, K99NS105915), Dr. Miriam and Sheldon G. Adelson, Paralyzed Veterans Foundation of America, American Australian Fellowship, Wing for Life and Microscopy Core Resource of UCLA Broad Stem Cell Research Center.

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