PERK Activation Preserves the Viability and Function of Remyelinating Oligodendrocytes in Immune-Mediated Demyelinating Diseases

Abstract

Remyelination occurs in multiple sclerosis (MS) lesions but is generally considered to be insufficient. One of the major challenges in MS research is to understand the causes of remyelination failure and to identify therapeutic targets that promote remyelination. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum stress modulates cell viability and function under stressful conditions. There is evidence that PERK is activated in remyelinating oligodendrocytes in demyelinated lesions in both MS and its animal model, experimental autoimmune encephalomyelitis (EAE). In this study, we sought to determine the role of PERK signaling in remyelinating oligodendrocytes in MS and EAE using transgenic mice that allow temporally controlled activation of PERK signaling specifically in oligodendrocytes. We demonstrated that persistent PERK activation was not deleterious to myelinating oligodendrocytes in young, developing mice or to remyelinating oligodendrocytes in cuprizone-induced demyelinated lesions. We found that enhancing PERK activation, specifically in (re)myelinating oligodendrocytes, protected the cells and myelin against the detrimental effects of interferon-γ, a key proinflammatory cytokine in MS and EAE. More important, we showed that enhancing PERK activation in remyelinating oligodendrocytes at the recovery stage of EAE promoted cell survival and remyelination in EAE demyelinated lesions. Thus, our data provide direct evidence that PERK activation cell-autonomously enhances the survival and preserves function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases.

Activating transcription factor 6α deficiency exacerbates oligodendrocyte death and myelin damage in immune‐mediated demyelinating diseases

“…A number of studies show that ER stress is a critical player in regulating oligodendrocyte viability in MS and EAE (Lin & Popko, ; Stone & Lin, ; Way & Popko, ). Data from our laboratory and other groups demonstrate the cytoprotective effects of the PERK pathway on oligodendrocytes during EAE (Lin et al, ; Hussien et al, ). Moreover, we have generated a mouse model that allows for controllable expression of IFN‐γ, a key pro‐inflammatory cytokine in MS and EAE, in the CNS (Lin et al, ).…”

“…Some studies show that the IRE1‐XBP1 pathway is not activated in oligodendrocytes under normal or disease conditions (Hussien et al, ; Stone & Lin, ); however, other studies show opposite results (Mháille et al, ; Ní Fhlathartaigh et al, ; Naughton, McMahon, & FitzGerald, ). A number of studies demonstrate that the PERK branch can positively or negatively influence oligodendrocyte viability in myelin disorders (Southwood, Garbern, Jiang, & Gow, ; Lin, Harding, Ron, & Popko, ; Lin et al, , , ; Hussien, Cavener, & Popko, ). Nevertheless, despite observation of activation of the ATF6α branch in oligodendrocytes under normal and disease conditions (Mháille et al, ; Naughton et al, ; Stone & Lin, ), the effects of ATF6α activation on these cells remains unknown.…”

Atf6α deficiency suppresses microglial activation and ameliorates pathology of experimental autoimmune encephalomyelitis

“…Moderate PERK activation was protective on oligodendrocytes in the models of MS (Lin et al . , ), and, consistently, oligodendrocyte‐specific PERK deletion increased the susceptibility of mice to EAE (Hussien et al . ).…”

Endoplasmic reticulum stress and the unfolded protein response in disorders of myelinating glia

“…Using this transgenic mouse, the authors demonstrate that strong activation of PERK specifically in oligodendrocytes leads to impaired eIF2B activity in young developing mice, resulting in a VWMD-like phenotype including myelin loss and “foamy” oligodendrocytes (Lin et al, 2014b). Strong activation of PERK was accomplished by using mice homozygous for PLP/Fv2E-PERK with high doses of the small molecule dimerizer compared to moderate PERK activation, which has no effect on developmental myelination in hemizygous PLP/Fv2E-PERK mice with low doses of dimerizer (Lin et al, 2014a). This study provides evidence of cell autonomous decreased eIF2B activity in oligodendrocytes as causative in VWMD.…”

“…The authors propose that inhibition of eIF2B is biphasic in nature. Modest inhibition of eIF2B is protective (Lin et al, 2013, 2014a) while strong inhibition of eIF2B, such as would happen with the combination of eIF2B mutation and phosphorylation of eIF2α by ER stress, is damaging to oligodendrocytes during active myelination and may explain the severe demyelination seen in VWMD following acute stress (Lin et al, 2014b). This hypothesis deserves further investigation.…”