Cedars-Sinai researchers have extensively mapped the molecular activity of the brain and spinal cord, which is responsible for regulating the body’s response to central nervous system (CNS) disorders such as Alzheimer’s, Huntington’s disease and spinal cord injuries.
Research has 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 key 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 specific changes in the disorder’s molecular profiles.
The discovery, detailed in the peer-reviewed journal Nature, may help develop a wide range of new therapies aimed at specific activity of astrocytes to help treat various central nervous system conditions, such as multiple sclerosis and the stroke.
“There is a growing interest in targeting the reactivity of astrocytes as treatment strategies for CNS disorders,” said Joshua Burda, PhD, lead author and co-author of the study and assistant professor in the Department of Biomedical Sciences. in the Department of Neurology. “Understanding how different types of astrocyte responses are coordinated and the consequences of manipulating these responses will not only help us better understand central nervous system diseases, but can provide crucial information to enable the development of better therapies. for these conditions “.
The reactivity of astrocytes is a hallmark of virtually all injuries and diseases of the nervous system. However, 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 diversity of cellular transformations of astrocytes, each involving changes in gene expression. To learn more about the mechanisms that control these changes in astrocyte gene expression, Burda and his team first developed a bioinformatics tool to identify “transcriptional regulators of astrocyte reactivity” – specialized molecules that determine the gene expression – in various neurological lesions or diseases.
The method is based on the consensus of multiple types of data, including computational and biological experimental data, that must be aligned to positively identify these specialized molecules.
The researchers then used genetic analysis to validate transcriptional regulators of reactivity as the primary determinant of progression and outcome of CNS disorder.
Taken together, the results of these studies showed that controlling changes in reactive gene expression is very complex. The team of scientists also showed for the first time how a relatively small group of transcriptional regulators can interact to coordinate the altered expression of hundreds or even thousands of astrocyte reactivity genes.
“With this extensive data set, we can now begin to investigate and link these regulatory pathways of modular astrocyte genes with specific aspects and reactivity states associated with numerous common neurological disorders,” Burda said. “Ultimately, we would like to use this information to therapeutically improve adaptive responses while reducing the maladaptive aspects of astrocyte reactivity. I also hope that our findings will bring about a significant change in the way people think. and study the reactivity of astrocytes. “
The other co-author of the study is Michael Sofroniew, MD, PhD, Distinguished Professor in the Department of Neurobiology at UCLA. Other Cedars-Sinai authors include Burda Lab team members Keshav Suresh, PhD candidate in the Cedars-Sinai Biomedical Science Program, and Sarah McCallum, PhD, a postdoctoral fellow.
Funding: The research reported in this publication was supported by grants from the National Institutes of Health (NS084039, F32NS096858, K99NS105915), the Dr. Miriam and Sheldon G. Adelson, Paralyzed Veterans Foundation of America, American Australian Fellowship, Wing for Life, and the basic microscopy resource from the UCLA Broad Stem Cell Research Center.