Dynamic Proteome Changes in Cuprizone-Induced Demyelination and Remyelination in the Mouse Brain

This study aimed to gain insights into the dynamic proteome
changes
and underlying molecular mechanisms of de/remyelination in a cuprizone
model, a widely used preclinical model of multiple sclerosis (MS).
Longitudinal sampling of control or cuprizone-treated mouse brains
was executed at 6 time points over 6 weeks. Data analysis included
8489 quantified proteins. Differential proteomic and GO analyses revealed
that 5.9% of the quantified proteome was altered, including reported
and novel de/remyelination-relevant protein changes and underlying
pathways. We found that oligodendrocyte proteins (Fa2h and Ugt8) were
significantly changed during demyelination, suggesting that dysregulated
sphingolipid metabolism in MS may stem from oligodendrocyte pathology.
Importantly, we showed that the cholesterol biosynthesis pathway was
the most enriched biological process in a subset of significantly
changed proteins, where myelination was highly enriched. We further
validated the changes in the cholesterol biosynthesis pathway through
targeted GC–MS analysis of intermediate sterols, supporting
the critical role of cholesterol biosynthesis in de/remyelination.
Unexpectedly, changes of myelin-associated proteins, Mbp and Plp1,
were minimal, while Ermn showed significant reduction tracking with
demyelination, indicating that some myelin protein changes are more
sensitive to demyelination. Together with a list of significantly
altered proteins, the results of this study could benefit future remyelination
research.