The unfolded protein response in multiple sclerosis

Stone, Sarrabeth; Lin, Wensheng

doi:10.3389/fnins.2015.00264

Cited by 80 publications

(89 citation statements)

References 134 publications

(203 reference statements)

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“…Previous studies have emphasized important roles of PERK signaling in oligodendrocyte survival and remyelination in MS/EAE (Lin and Popko ; Stone and Lin ). It was also recently reported that deletion of GRP78 in oligodendrocytes caused severe impairment in myelination both in physiological and pathological conditions (Hussien et al .…”

Section: Discussionmentioning

confidence: 99%

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

Ishii

et al. 2016

Journal of Neurochemistry

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Accumulating evidence suggests a critical role for the unfolded protein response in multiple sclerosis (MS) and in its animal model, experimental autoimmune encephalomyelitis (EAE). In this study, we investigated the relevance of activating transcription factor 6α (ATF6α), an upstream regulator of part of the unfolded protein response, in EAE. The expressions of ATF6α‐target molecular chaperones such as glucose‐regulated protein 78 (GRP78) and glucose‐regulated protein 94 (GRP94) were enhanced in the acute inflammatory phase after induction of EAE. Deletion of Atf6α suppressed the accumulation of T cells and microglia/macrophages in the spinal cord, and ameliorated the clinical course and demyelination after EAE induction. In contrast to the phenotypes in the spinal cord, activation status of T cells in the peripheral tissues or in the culture system was not different between two genotypes. Bone marrow transfer experiments and adoptive transfer of autoimmune CD4+ T cells to recipient mice (passive EAE) also revealed that CNS‐resident cells are responsible for the phenotypes observed in Atf6α−/− mice. Further experiments with cultured cells indicated that inflammatory response was reduced in Atf6α−/− microglia, but not in Atf6α−/− astrocytes, and was associated with proteasome‐dependent degradation of NF‐κB p65. Thus, our results demonstrate a novel role for ATF6α in microglia‐mediated CNS inflammation. We investigated the relevance of ATF6α, an upstream regulator of part of the UPR, in EAE. Deletion of Atf6α suppressed inflammation, and ameliorated demyelination after EAE. Bone marrow transfer experiments and adoptive transfer of autoimmune CD4+ T cells revealed that CNS‐resident cells are responsible for the phenotypes in Atf6α−/− mice. Furthermore, inflammatory response was reduced in Atf6α−/− microglia, and was associated with degradation of NF‐κB p65. Our results demonstrate a novel role for ATF6α in microglia‐mediated inflammation. Cover image for this issue: doi: .

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Section: Discussionmentioning

confidence: 99%

“…Accumulating evidence has suggested a crucial role for the UPR in the pathogenesis of various myelin disorders including MS, Pelizaeus–Merzbacher disease (PMD), and their animal models (for review, Lin and Popko ; Stone and Lin ). PMD is an X chromosome ‐linked demyelinating disease which is caused by mutations in the gene proteolipid protein‐1 (PLP1).…”

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confidence: 99%

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

Ishii

et al. 2016

Journal of Neurochemistry

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“…Although the IRE1 branch is the most conserved part of the UPR, activation of this branch in oligodendrocytes is controversial. 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, ).…”

Section: Introductionmentioning

confidence: 99%

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

Stone

Jamison

et al. 2018

Glia

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Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) play a critical role in immune-mediated demyelinating diseases, including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), by regulating the viability of oligodendrocytes. Our previous studies show that activation of the PERK branch of the UPR protects myelinating oligodendrocytes against ER stress in young, developing mice that express IFN-γ, a key pro-inflammatory cytokine in MS and EAE, in the CNS. Several studies also demonstrate that PERK activation preserves oligodendrocyte viability and function, protecting mice against EAE. While evidence suggests activation of the ATF6α branch of the UPR in oligodendrocytes under normal and disease conditions, the effects of ATF6α activation on oligodendrocytes in immune-mediated demyelinating diseases remain unknown. Herein, we showed that ATF6α deficiency had no effect on oligodendrocytes under normal conditions. Interestingly, we showed that ATF6α deficiency exacerbated ER stressed-induced myelinating oligodendrocyte death and subsequent myelin loss in the developing CNS of IFN-γ-expressing mice. Moreover, we found that ATF6α deficiency increased EAE severity and aggravated EAE-induced oligodendrocyte loss and demyelination, without affecting inflammation. Thus, these data suggest the protective effects of ATF6α activation on oligodendrocytes in immune-mediated demyelinating diseases.

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“…In addition, reduced demyelination was also observed. As the blood-CNS barrier is often compromised in neuroinflammatory diseases such as MS or EAE, one can consider a possibility that in addition to reducing inflammatory phenotype of T cells, CX-5461 had also at least some direct beneficial effects on neuroinflammation-challenged oligodendrocytes including attenuation of the cytotoxic ER stress response [25]. …”

Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of spinal cord injury-stimulated ribosomal biogenesis does not affect locomotor outcome

Kilańczyk

Andres

Hallgren

et al. 2017

Neuroscience Letters

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After unresolved endoplasmic reticulum stress, recovery of protein synthesis including increased expression of ribosomal components and translation factors may induce cell death. Using a mouse model of moderate contusive spinal cord injury (SCI) at the T9 level, upregulation of ribosomal biogenesis was observed in the injury epicenter at 24 h after trauma. Such upregulation coincided with endoplasmic reticulum stress response as previously reported in this model. It was also accompanied by changes in expression of many other genes associated with translational regulation. Systemic treatment with a pharmacological inhibitor of RNA-Polymerase-1, BMH-21 reduced rRNA transcription in the spinal cord. Moreover, in the injury epicenter, treatment with BMH-21 increased expression of oligodendrocyte-specific transcripts including Mbp and Cldn11 at 3 days post injury. Although such findings may suggest at least transient reduction of oligodendrocyte death, locomotor outcome was mostly unaffected except slightly accelerated recovery of hindlimb function at week 2 post-injury. Therefore, at least in mice, RNA-Polymerase-1 does not appear to be a robust target for therapies to protect spinal cord tissue after contusion. However, these findings raise an interesting possibility that altered rate of ribosomal biogenesis contributes to the apparent translational reprogramming after contusive SCI. Such a reprogramming could be a major regulator of SCI-induced gene expression.

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The unfolded protein response in multiple sclerosis

Cited by 80 publications

References 134 publications

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

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

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

Pharmacological inhibition of spinal cord injury-stimulated ribosomal biogenesis does not affect locomotor outcome

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