The Cellular Landscape of MS: Decoding Differences Between RRMS and SPMS

Multiple sclerosis (MS) is a disease that affects the central nervous system, disrupting communication between the brain and the body. It's often characterized by the formation of lesions, or areas of damage, in the brain and spinal cord. What's less understood are the changes happening in the brain outside of these lesions, in areas that appear normal. A new study uses a powerful technique called single-nucleus RNA sequencing (snRNA-seq) to investigate these "normal-appearing" brain regions in individuals with different forms of MS, and the results are fascinating.

What the Researchers Did
Researchers analyzed postmortem brain tissue from people with relapsing-remitting MS (RRMS), the most common form of MS, and secondary-progressive MS (SPMS), a more advanced form of the disease. They focused on the prefrontal cortex, a region involved in higher-level thinking. Using snRNA-seq, they examined the genetic material of over 33,000 individual nuclei from these brain samples, allowing them to identify different cell types and analyze their gene expression.

Key Findings
Here are some of the significant discoveries from the study:

* Excitatory Neuron Differences: The study found that excitatory neurons, which are responsible for sending activating signals in the brain, showed different gene expression patterns in RRMS compared to SPMS. RRMS brains showed lower expression of genes associated with these neurons, suggesting potential neuronal loss or dysfunction. SPMS brains, on the other hand, showed an increase in genes related to ion channels which may indicate a channelopathy-like defect which can cause axonal degeneration.

* Oligodendrocyte Changes: Oligodendrocytes (OLs) are cells that produce myelin, the protective coating around nerve fibers. The research found that OLs in SPMS brains showed lower expression of myelin-related genes compared to RRMS brains, suggesting a potential vulnerability that could contribute to the loss of myelin in MS. RRMS OLs also showed signs of cellular stress, which might eventually lead to OL loss in SPMS. Furthermore, genes involved in sphingolipid synthesis were downregulated in SPMS, suggesting problems with myelin synthesis as MS progresses.

* Astrocyte Activity: Astrocytes, another type of brain cell, showed a more reactive phenotype in RRMS compared to SPMS. RRMS astrocytes expressed markers associated with inflammation, while SPMS astrocytes expressed more genes related to antioxidants, suggesting different responses to the disease in each form of MS. These differences suggest that astrocytes may have different roles in the progression of the disease. There was also evidence of immediate-early astrocytes (ieAstrocytes), which have previously been found in animal models of MS, and which were more prevalent in RRMS samples.

* Fingolimod and Sphingosine Kinases: A key part of the study focused on why the drug fingolimod, which is effective for RRMS, isn't effective for progressive forms of MS. The researchers discovered that SPMS brains had a significant reduction in the expression of sphingosine kinases (SPHK1 and SPHK2), enzymes needed to activate fingolimod. This reduction was found in astrocytes and pericytes. In an animal model where these enzymes were removed from astrocytes, fingolimod was no longer effective. This suggests that the reduced SPHK1/2 expression in the brains of people with SPMS is a potential reason why fingolimod doesn’t work for progressive forms of MS.

Why This Matters
This study has important implications for understanding MS and developing new treatments. Here’s why:

* Beyond the Lesions: The findings highlight that significant changes occur in the brain outside of the visible lesions, indicating that MS is not just a disease of localized damage. This could explain why some people experience neurological decline even when they don't have new lesions.

* Cell-Specific Changes: The study shows that different cell types react differently to MS, emphasizing that treatments may need to be tailored to target specific cells.

* Fingolimod Mechanism: The findings pinpoint that the effectiveness of fingolimod may rely on sphingosine kinases in astrocytes and pericytes, providing insights into why it doesn't work in progressive MS. This highlights the importance of developing treatments that don't rely on SPHK activation, such as siponimod, which has been shown to be effective for SPMS.

What's Next
This study provides a wealth of data and opens many avenues for further research. Future studies will hopefully be able to confirm these results with larger sample sizes and further dissect the complex interactions of cells in MS brains. By further exploring the roles of these different cell types and signaling pathways, we could find more effective treatments for all forms of MS.

This research underscores the importance of understanding MS at the cellular and molecular level to develop effective therapies. It is a significant step forward in our fight against this devastating disease.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Kihara, Y., Zhu, Y., Jonnalagadda, D., Romanow, W., Palmer, C., Siddoway, B., ... & Chun, J. (2022). Single-nucleus RNA-seq of normal-appearing brain regions in relapsing-remitting vs. secondary progressive multiple sclerosis: implications for the efficacy of fingolimod. Frontiers in Cellular Neuroscience, 16, 918041.