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 concurrent advancing neurological disability, although the underlying molecular mechanisms remain uncertain. To investigate the molecular basis of PMS, we used mass spectrometry to define proteomic profiles and specific protein changes in matched CNS tissues (cortex, white matter, and demyelinated 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 including neurons, astrocytes, microglia, oligodendrocyte progenitor cells (OPCs) and CNS tissues from PMS mouse models. Collagen-containing 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 matched ODC tissues. These enriched proteins showed increased abundance in astrocytes and microglia compared to neurons and OPCs. 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 also providing new diagnostic and therapeutic options for future investigation.