Alexander disease mutations differentially sensitize GFAP to oxidative damage and network disruption

The type III intermediate filament protein GFAP plays key roles in astrocyte and brain homeostasis. Mutations in GFAP can result in Alexander’s disease (AxD), a severe neurodegenerative disease. Studies in AxD models indicate that oxidative stress may be an important pathogenic factor. Expression of certain GFAP AxD mutants in cells can provoke oxidative stress and potentially contribute to a pathogenic cycle since GFAP itself is an important target of oxidants. In order to understand the molecular mechanisms involved, we have carried out a detailed LC-MS/MS characterization of posttranslational modifications formed on recombinant GFAP wild-type and AxD mutants (R79C, R239C and E373K), in response to in vitro treatment with the biologically-relevant oxidants H2O2, HOCl and ONOOH.