Brain and neural cell type proteomics reveal extracellular matrix proteins enriched in progressive multiple sclerosis

Progressive multiple sclerosis (PMS) is an autoimmune demyelinating disease of the central nervous system (CNS) in humans. PMS is defined by neuroinflammation and axonal damage with advancing neurological disabilities, although the underlying molecular mechanisms remain uncertain. To gain insight into the proteomic aspects of PMS, we used mass spectrometry to investigate proteomic profiles and specific protein changes in matched CNS tissues (white matter, cortex, and lesions) from persons with PMS and age/sex-matched other disease controls (ODCs). These studies were examined further using proteomes of primary human neural cell types (e.g., neurons, astrocytes, microglia, oligodendrocyte progenitor cells/OPCs) and CNS tissues from PMS mouse models. Extracellular matrix (ECM) related proteins, including the annexin, S100, and AHNAK protein families, were significantly enriched in PMS white matter, especially within demyelinated lesions compared to ODC tissues. These enriched proteins showed increased abundance in astrocytes, microglia, and OPCs compared to neurons. Annexin, S100, and AHNAK family proteins were also increased in the CNS of the cuprizone and experimental autoimmune encephalitis mouse models. These findings highlight the importance of ECM protein induction in CNS glial cells during PMS while providing potential therapeutic targets for future investigation.