Unlocking the Mysteries of Multiple Sclerosis: A New Focus on Brain Cells and Cholesterol
Multiple sclerosis (MS) is a complex immune-mediated neurodegenerative disease that affects the central nervous system (CNS), causing a range of symptoms from walking difficulties to vision problems and cognitive issues. The unpredictable nature of MS, with its varied symptoms and severity from person to person, has long posed a challenge for developing effective treatments. A recent study published in the *Proceedings of the National Academy of Sciences* (PNAS) sheds new light on this disease by taking a closer look at specific cells in different areas of the brain.
The "One-Size-Fits-All" Approach May Not Be Optimal
Traditional approaches to studying neurological diseases often involve examining gene expression in whole CNS tissues. However, the brain contains many different types of cells, and their composition can change during a disease. This means that changes in gene expression might be influenced by alterations in the cellular makeup of the tissue and not just the disease itself. To overcome this limitation, researchers in this study used a cell-specific and region-specific transcriptomics approach. They focused on astrocytes, a type of brain cell that plays a crucial role in supporting neurons.
Astrocyte Focus
Astrocytes were the focus of this study because they are involved in the formation of scar tissue in MS lesions. Furthermore, studies have shown that astrocytes can have both beneficial and detrimental roles in neuroinflammatory diseases. Using a technique called RiboTag, the researchers were able to isolate RNA from astrocytes in different regions of the brain (spinal cord, cerebellum, cerebral cortex, and hippocampus) of mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. This allowed them to examine gene expression changes in astrocytes during EAE, while differentiating between different brain regions.
Key Findings: Cholesterol and the Brain
The results of this study revealed some interesting and potentially important differences in gene expression in astrocytes between different brain regions during EAE. The most significant finding was that genes involved in cholesterol synthesis were decreased in astrocytes in the spinal cord and optic nerve during EAE. This was unexpected because cholesterol is essential for the proper functioning of the CNS.
* Cholesterol's role in the CNS: Unlike the rest of the body, cholesterol in the brain is not obtained from diet and does not cross the blood-brain barrier. Instead, it is produced by cells within the brain. In the adult brain, astrocytes are the main cells producing cholesterol. This cholesterol is then transported to neurons for making membranes and synapses, and to oligodendrocytes to produce myelin.
* Cholesterol synthesis reduction in MS: The study suggests that decreased cholesterol synthesis in astrocytes during EAE and MS could lead to a reduced amount of cholesterol available for neurons and oligodendrocytes. This could impair the repair of damaged myelin and prevent new synapse formation.
* Region-specific effects: The decrease in cholesterol synthesis was more pronounced in spinal cord and optic nerve astrocytes compared to those in the hippocampus and cerebral cortex. This regional difference suggests that treatments for MS should consider specific brain regions to best target the underlying issues in MS.
Targeting Cholesterol for Treatment
These findings prompted the researchers to investigate treatments that could restore cholesterol levels in the brain. They tested a drug called CS-6253, which is known to increase the transport of cholesterol. This drug was able to increase cholesterol synthesis gene expression in astrocytes of both normal and EAE mice and helped improve motor function in the EAE mice. These results highlight the potential of targeting cholesterol synthesis in astrocytes as a new therapeutic strategy for MS.
Confirmation in Human MS Tissue
To confirm the findings in humans, the researchers examined gene expression in optic chiasm tissue (part of the visual pathway) from MS patients and healthy controls. Similar to the findings in mice, they observed a decrease in cholesterol synthesis gene expression in the optic chiasm of MS patients. This provides further evidence that the role of cholesterol in MS is significant in both preclinical models and human patients.
Implications for MS Treatment
This study suggests a new approach for treating MS: disability-specific treatments tailored to the specific regions of the brain affected by MS. The researchers propose that treatments should be focused on reversing the molecular signature of the disease in the specific neurological pathway. This could potentially be more effective than current treatments which aim to reduce a composite of symptoms.
In Conclusion
This research provides a significant step forward in our understanding of the complex mechanisms of MS. By using a cell-specific and region-specific approach, the study highlights the importance of astrocytes and cholesterol metabolism in MS. The findings suggest that targeting cholesterol homeostasis in specific brain regions could potentially be a novel therapeutic approach for this challenging disease. Further research in this area will be critical to develop new treatments and improve the lives of people affected by MS.
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:
Itoh, N., Itoh, Y., Tassoni, A., Ren, E., Kaito, M., Ohno, A. I., ... & Voskuhl, R. R. (2018). Cell-specific and region-specific transcriptomics in the multiple sclerosis model: Focus on astrocytes. Proceedings of the National Academy of Sciences, 115(2), E302-E309.
