Abstract:
:Cuprizone intoxication is a common animal model used to test myelin regenerative therapies for the treatment of diseases such as multiple sclerosis. Mice fed this copper chelator develop reversible, region-specific oligodendrocyte loss and demyelination. While the cellular changes influencing the demyelinating process have been explored in this model, there is no consensus about the biochemical mechanisms of toxicity in oligodendrocytes and about whether this damage arises from the chelation of copper in vivo. Here we have identified an oligodendroglial cell line that displays sensitivity to cuprizone toxicity and performed global metabolomic profiling to determine biochemical pathways altered by this treatment. We link these changes with alterations in brain metabolism in mice fed cuprizone for 2 and 6 weeks. We find that cuprizone induces widespread changes in one-carbon and amino acid metabolism as well as alterations in small molecules that are important for energy generation. We used mass spectrometry to examine chemical interactions that are important for copper chelation and toxicity. Our results indicate that cuprizone induces global perturbations in cellular metabolism that may be independent of its copper chelating ability and potentially related to its interactions with pyridoxal 5'-phosphate, a coenzyme essential for amino acid metabolism.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Taraboletti A,Walker T,Avila R,Huang H,Caporoso J,Manandhar E,Leeper TC,Modarelli DA,Medicetty S,Shriver LPdoi
10.1021/acs.biochem.6b01072subject
Has Abstractpub_date
2017-03-14 00:00:00pages
1518-1528issue
10eissn
0006-2960issn
1520-4995journal_volume
56pub_type
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