Myelin Basic Protein Post-Translational Modifications Orchestrate Astrocyte Regulatory Networks

Area of Science:

• Neuroimmunology
• Glial Cell Biology
• Molecular Neuroscience

Background:

• Multiple sclerosis (MS) pathogenesis involves immune-mediated myelin damage and glial cell activation.
• Astrocyte responses are crucial in modulating neuroinflammation and repair processes within the central nervous system.
• Post-translational modifications (PTMs) of myelin basic protein (MBP) may influence glial cell behavior.

Purpose of the Study:

• To investigate how different charge isomers of MBP (native C1, phosphorylated C4, citrullinated C8) modulate rat astrocyte phenotypes.
• To characterize the cytokine profiles, metabolic receptor activation (LXR), and epigenetic changes induced by these MBP isomers.
• To elucidate the distinct functional outcomes of MBP PTMs on astrocyte-mediated neuroinflammation and repair.

Main Methods:

• Treatment of primary rat astrocytes with three MBP charge isomers: C1 (native), C4 (phosphorylated), and C8 (citrullinated).
• Quantification of a broad panel of cytokines and assessment of regulatory markers, including LXR receptor and global DNA methylation.
• Functional analysis of astrocyte responses to each isomer to determine distinct phenotypic outcomes.

Main Results:

• MBP isomer C1 upregulated LXR and reduced DNA methylation, attenuating pro-inflammatory cytokines (IL-1β, IL-6, GM-CSF) while increasing IL-10.
• MBP isomer C4 showed moderate LXR activation and induced specific chemokines (CX3CL1, CCL20), VEGF-A, and TIMP-1.
• MBP isomer C8 failed to activate LXR or alter methylation, triggering a robust pro-inflammatory response with increased IL-1α/β, TNF-α, and GM-CSF, alongside elevated reparative markers.

Conclusions:

• Distinct MBP PTMs drive unique astrocyte phenotypes via integrated cytokine, metabolic, and epigenetic pathways.
• MBP C1 promotes immune regulation and repair, C4 presents a mixed inflammatory/reparative profile, and C8 exacerbates neuroinflammation.
• Understanding modified MBP's role in astrocyte modulation offers mechanistic insights into MS lesion evolution and suggests astrocyte-targeted therapeutic strategies for remyelination.