The Gas6/TAM Receptor System: A Potential Key to Understanding White Matter Damage in Multiple Sclerosis
A recent study has shed light on the role of the Gas6/TAM receptor system in the neurodegenerative processes that influence demyelination and remyelination in multiple sclerosis (MS). This blog post will explore the findings of this research and their potential implications for understanding and treating MS.
Background on Multiple Sclerosis and the Gas6/TAM System
MS is an immune-mediated disease where the immune system attacks the myelin sheaths that protect nerve fibers in the central nervous system (CNS). This leads to inflammation and damage to myelin and axons, contributing to disability. Macrophages and microglia, which secrete pro-inflammatory cytokines, play a key role in this process.
The Growth arrest-specific 6 (Gas6)/TAM (Tyro3, Axl, and Mer) receptor system is involved in various physiological processes like cell migration, adhesion, growth, and survival. Previous animal studies suggested its involvement in autoimmune neuroinflammatory conditions, including MS. Specifically, mice lacking Gas6 showed heightened demyelination and delayed remyelination. Tyro3, which is widely expressed in the CNS white matter, regulates myelination.
Study Design and Methods
The study investigated the association between Gas6/TAM receptor/Gas6 ligand levels and degeneration and repair processes in patients with relapsing-remitting MS (RRMS) and progressive MS (PMS). The researchers analyzed soluble Gas6/TAM biomarkers in cerebrospinal fluid (CSF) from patients with RRMS (n = 40), PMS (n = 20), and healthy controls (HC) (n = 25). Brain volumes, myelin content (MyC), and white matter (WM) were measured using synthetic magnetic resonance imaging (MRI) at baseline, 12 months, and 60-month follow-up.
Key Findings
* Elevated Gas6/TAM Levels in PMS: Baseline concentrations of Tyro3, Axl, and Gas6 were significantly higher in PMS compared to RRMS and HC. Mer was higher in PMS compared to HC.
* Association with White Matter and Myelin Integrity: Tyro3 and Gas6 were associated with reduced WM and MyC at 60 months. Patients with evidence of remyelination had lower baseline soluble Tyro3 and Gas6.
* Correlation with Neuroaxonal Damage Markers: Baseline Tyro3 and Gas6 concentrations correlated with CSF GFAP, a marker of astrogliosis. Gas6 also correlated with serum GFAP (sGFAP). In RRMS patients, Tyro3 and Gas6 correlated with CSF NfL at 12 months follow-up.
* No Influence of DMT on Gas6/TAM: Except for Mer, Gas6/TAM concentrations did not change significantly with disease-modifying therapy (DMT) in RRMS.
Implications for Multiple Sclerosis
These findings suggest that the Gas6/TAM receptor system plays a role in the loss of white matter integrity in MS patients. The elevated levels of Gas6/TAM biomarkers in PMS patients indicate involvement in the degenerative processes driving progressive MS. The association of Tyro3 and Gas6 with reduced WM and MyC suggests that these factors may contribute to demyelination and ineffective remyelination.
The correlation between Gas6/TAM and GFAP, a marker of astrocyte activation, reinforces the idea of cross-talk between astrocytes, oligodendrocytes, and microglia in driving chronic neurodegeneration in MS.
Prior Research and GWAS Findings
Previous studies in animal models have shown that loss of Tyro3 leads to delayed myelination and altered myelin thickness in the CNS. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) within the MerTK gene as linked to MS susceptibility.
Limitations
The study acknowledges limitations such as a relatively small sample size, which may limit statistical power and generalizability. The sampling before and after treatment initiation was only 12 months apart. However, the follow-up time for MyC and WM was 60 months, which is sufficient to capture meaningful changes.
Conclusion
This study provides evidence for the involvement of the Gas6/TAM receptor system, particularly Tyro3 and Gas6, in the loss of white matter integrity and ineffective remyelination in MS. These findings contribute to our understanding of the complex neurodegenerative processes underlying MS and may offer potential targets for future therapeutic interventions.
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:
Rosenstein, I., Novakova, L., Kvartsberg, H. et al. Tyro3 and Gas6 are associated with white matter and myelin integrity in multiple sclerosis. J Neuroinflammation 21, 320 (2024).
