AI Article Synopsis

  • Demyelinated brain lesions are caused by autoimmune diseases like multiple sclerosis and are linked to damage of oligodendroglial cells, mainly due to activated microglia producing nitric oxide, which causes myelin damage.
  • Glutaredoxin 2 has been found to inhibit the formation of harmful peroxynitrite by converting nitric oxide into a less harmful compound and plays a crucial role in protecting oligodendrocyte cells and preserving myelin structure.
  • The protective mechanism of glutaredoxin 2 is not related to its usual enzymatic function but rather involves the reconfiguration of its iron-sulfur cluster; thus, enhancing glutathione levels could be a potential therapeutic strategy for treating inflammatory demyelination.

Article Abstract

Demyelinated brain lesions, a hallmark of autoimmune neuroinflammatory diseases like multiple sclerosis, result from oligodendroglial cell damage. Activated microglia are considered a major source of nitric oxide and subsequent peroxynitrite-mediated damage of myelin. Here, we provide biochemical and biophysical evidence that the oxidoreductase glutaredoxin 2 inhibits peroxynitrite formation by transforming nitric oxide into dinitrosyl-diglutathionyl-iron-complexes. Glutaredoxin 2 levels influence both survival rates of primary oligodendrocyte progenitor cells and preservation of myelin structure in cerebellar organotypic slice cultures challenged with activated microglia or nitric oxide donors. Of note, glutaredoxin 2-mediated protection is not linked to its enzymatic activity as oxidoreductase, but to the disassembly of its uniquely coordinated iron-sulfur cluster using glutathione as non-protein ligand. The protective effect of glutaredoxin 2 is connected to decreased protein carbonylation and nitration. In line, brain lesions of mice suffering from experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, show decreased glutaredoxin 2 expression and increased nitrotyrosine formation indicating that this type of protection is missing in the inflamed central nervous system. Our findings link inorganic biochemistry to neuroinflammation and identify glutaredoxin 2 as a protective factor against neuroinflammation-mediated myelin damage. Thus, improved availability of glutathione-coordinated iron-sulfur clusters emerges as a potential therapeutic approach in inflammatory demyelination.

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Source
http://dx.doi.org/10.1002/glia.23178DOI Listing

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