Pathological abnormalities in progressive multiple sclerosis: insights from ultrastructural and surface proteomic studies

Multiple sclerosis (MS) is characterized by myelin loss, inflammation and neurodegeneration. After episodes of myelin loss, remyelination occurs but repair efficiency declines with aging. MS symptoms progressively worsen, independently of relapses, driven by diffuse pathology in non-demyelinated brain tissue. Current treatments target the immune system but do not promote remyelination or halt progression. In this thesis, I used advanced electron microscopy and surface proteomics to obtain insights in abnormalities linked with remyelination failure and diffuse pathology.
Ultrastructural analysis of non-demyelinated white matter brain tissue, with large-scale scanning transmission electron microscopy (STEM) revealed loss of smaller myelinated axons in MS, swelling of remaining myelinated axon with adjusted myelin thickness and limited mitochondrial adaptation to increased axon size. These changes may increase vulnerability of MS white matter. A rare feature of some myelinated axons was non homogenous myelin membrane layers, which we termed ‘belted myelin’. Further high-resolution STEM and energy dispersive X-ray analysis indicate the belted appearance reflects iron-affinity differences likely associated with newly formed myelin. With in situ cell surface proteomics, I identified differentially abundant and unique cell surface proteins in non-demyelinated MS brain tissue, highlighting potential therapeutic targets for diffuse MS pathology. Unexpectedly, a subset of white matter MS lesions contained excitatory axodendritic synapses, correlating with the presence of neuronal nuclei and small, thinly myelinated axons. These axons are likely newly generated by local neurogenesis, reshaping our view on remyelination failure.
Together, our findings reveal subtle myelin changes in NAWM and synapses in white matter lesions, offering potential for therapies targeting remyelination failure and MS progression.