Oligodendrocyte (OL) damage and astrocyte activation are key features in multiple sclerosis (MS) plaques as well as in inflamed lesions of rodents suffering from experimental autoimmune encephalomyelitis (EAE), an animal model which mimics many histopathological features of MS. To a large extent, inflammatory demyelination is paralleled by loss of OL in the lesions [
31‐
33]. To date, several factors were identified which govern OL susceptibility after an inflammatory attack in the CNS. Such factors comprise neurotrophic cytokines like ciliary neurotrophic factor, leukemia inhibitory factor, or other neurotrophic factors [
2,
19,
22]. Besides investigations on glial growth factors, recent studies suggest a role of oligodendroglial death or pro/anti-apoptotic pathways in models of demyelination. Among others, candidates include death pathways involving tumor necrosis factor receptors, Fas-FasL interaction, or tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) [
6,
7,
28,
29]. Yet, some of these studies reveal divergent roles of some pathways in toxic vs. autoimmune-mediated demyelination or in vitro vs. in vivo approaches. Thus, it is still tempting to investigate the role of further molecules implicated in the degeneration of CNS cells during autoimmune demyelination. Here, the family of 14-3-3 proteins may be of particular interest. In mammals, 14-3-3 proteins comprise seven distinct highly homologous, ubiquitously expressed isoforms (γ, β, ζ, η, σ, and τ), which represent about 1 % of the total soluble brain protein. 14-3-3 subunits are involved in a wide variety of physiological processes, including neuronal development, apoptosis, cell cycle control, and signal transduction [
42]. The extraordinary large number of more than 100 binding partners for 14-3-3 proteins suggests a role as major cellular regulator. To date, a plethora of studies describe a role of 14-3-3 proteins in the pathogenesis of chronic as well as acute neurodegenerative disorders, including Creutzfeldt-Jakob disease, Alzheimer’s disease, amyotrophic lateral sclerosis, or stroke [
37]. The function of 14-3-3 proteins in these conditions comprises several mechanisms, which may include basic cellular processes like induction, but also the prevention from apoptotic processes depending on the cell type or disease model studied. To assess the role of 14-3-3 proteins in autoimmune demyelination, we employ mice deficient for the 14-3-3 gamma subunit (14-3-3 γ −/− mice). If not challenged, these mice display a normal anatomy and behavior. Upon inoculation with pathogenic prion protein, survival rates in 14-3-3 γ −/− mice are unchanged [
43]. However, 14-3-3 γ deficiency may impair the recruitment of activation-induced cytidine deaminase to immunoglobulin H switch regions and is thus involved in class switch DNA recombination, a mechanism that diversifies the biological antibody response [
50].
Here, we investigate the role of 14-3-3 γ protein in glia cell culture and in myelin oligodendrocyte glycoprotein (MOG) peptide 35-55-induced EAE, a model of neuroinflammation with neurodegenerative features. Our data identify a pivotal role of 14-3-3 γ deficiency for OL apoptosis in neuroinflammation.