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White matter integrity requires continuous myelin synthesis at the inner tongue

ABSTRACT: Myelin, the electrically insulating axonal sheath, is composed of lipids and proteins with exceptionally long lifetime. Using 3D electron microscopy, mass spectrometry imaging, and quantitative proteome analysis, we addressed the question how myelin function is affected by myelin turnover. We studied the integrity of myelinated tracts after experimentally preventing the formation of new myelin in the CNS of adult mice by an inducible myelin basic protein (Mbp) null allele. Recombined oligodendrocytes continued to express myelin genes, but failed to establish MBP-dependent compaction of myelin sheaths. Abundance changes of myelin proteins upon Mbp ablation were analyzed in whole optic nerve lysates at different time points and compared with shiverer mice. This naturally occurring mutant is inable to developmentally form compact myelin due to the lack of MBP and served as proxy for the demyelination endpoint. Label-free protein quantification using an ion mobility-enhanced data-independent acquisition (DIA) workflow with alternating low and elevated energy (referred to as UDMS^E) revealed that numerous myelin proteins are reduced in abundance, while microglia and astrocyte markers were increased, indicative of neuropathology. Taken together, we observed an axonal pathology with about 50% myelin loss after 20 weeks and concluded that functional axon-myelin units require the continuous incorporation of new myelin membranes.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Oligodendrocyte, Optic Nerve

SUBMITTER: Olaf Jahn

LAB HEAD: PD Dr. Olaf Jahn

PROVIDER: PXD025180 | Pride | 2022-01-14

REPOSITORIES: Pride

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