Oligodendrocyte-Specific Activation of PERK Signaling Protects Mice against Experimental Autoimmune Encephalomyelitis

Lin, Wensheng; Lin, Yifeng; Li, Jin; Fenstermaker, Ali G.; Way, Sharon W.; Clayton, Benjamin L.L.; Jamison, Stephanie; Harding, Heather P.; Ron, David; Popko, Brian

doi:10.1523/jneurosci.1636-12.2013

Cited by 101 publications

(180 citation statements)

References 58 publications

(88 reference statements)

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“…7D). As expected, expression of myelin genes in rsh mice is decreased approximately twofold (Mitchell et al, 1992), and this phenotype is not altered by constitutive CHOP expression. Together, these data demonstrate that CHOP is a relatively neutral transcription factor under homeostatic conditions and that excess CHOP does not modify the overall activity of the UPR under metabolic stress conditions.…”

Section: Constitutive Chop Does Not Alter Expression Of Upr- Apoptossupporting

confidence: 81%

Overexpression of CHOP in Myelinating Cells Does Not Confer a Significant Phenotype under Normal or Metabolic Stress Conditions

Southwood¹,

Fyk‐Kolodziej²,

Maheras³

et al. 2016

J. Neurosci.

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The PKR-like endoplasmic reticulum kinase (PERK) pathway of the unfolded protein response (UPR) is protective against toxic accumulations of misfolded proteins in the endoplasmic reticulum, but is thought to drive cell death via the transcription factor, CHOP. However, in many cell types, CHOP is an obligate step in the PERK pathway, which frames the conundrum of a prosurvival pathway that kills cells. Our laboratory and others have previously demonstrated the prosurvival activity of the PERK pathway in oligodendrocytes. In the current study, we constitutively overexpress CHOP in myelinating cells during development and into adulthood under normal or UPR conditions. We show that this transcription factor does not drive apoptosis. Indeed, we observe no detriment in mice at multiple levels from single cells to mouse behavior and life span. In light of these data and other studies, we reinterpret PERK pathway function in the context of a stochastic vulnerability model, which governs the likelihood that cells undergo cell death upon cessation of UPR protection and while attempting to restore homeostasis.

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Section: Constitutive Chop Does Not Alter Expression Of Upr- Apoptossupporting

confidence: 81%

Overexpression of CHOP in Myelinating Cells Does Not Confer a Significant Phenotype under Normal or Metabolic Stress Conditions

Southwood¹,

Fyk‐Kolodziej²,

Maheras³

et al. 2016

J. Neurosci.

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“…To prevent movement of the slice preparations during observation, a nylon net glued to a small silver wire ring was placed over the preparations. The rate of cell movement is closely related to the temperature of the medium; lowering the medium temperature slows cell movement (Rakic and Komuro, 1995;Lin et al, 2013). Therefore, the chamber temperature was kept at 37.0 Ϯ 0.5°C using a temperature controller (TC-202; Medical System), and the slices were provided with constant gas flow (95% O 2 , 5% CO 2 ).…”

Section: Methodsmentioning

confidence: 99%

Myelin Proteolipid Protein Complexes with v Integrin and AMPA Receptors In Vivo and Regulates AMPA-Dependent Oligodendrocyte Progenitor Cell Migration through the Modulation of Cell-Surface GluR2 Expression

Harlow

Saul²,

Komuro

et al. 2015

Journal of Neuroscience

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In previous studies, stimulation of ionotropic AMPA/kainate glutamate receptors on cultured oligodendrocyte cells induced the formation of a signaling complex that includes the AMPA receptor, integrins, calcium-binding proteins, and, surprisingly, the myelin proteolipid protein (PLP). AMPA stimulation of cultured oligodendrocyte progenitor cells (OPCs) also caused an increase in OPC migration. The current studies focused primarily on the formation of the PLP-␣v integrin-AMPA receptor complex in vivo and whether complex formation impacts OPC migration in the brain. We found that in wild-type cerebellum, PLP associates with ␣v integrin and the calciumimpermeable GluR2 subunit of the AMPA receptor, but in mice lacking PLP, ␣v integrin did not associate with GluR2. Live imaging studies of OPC migration in ex vivo cerebellar slices demonstrated altered OPC migratory responses to neurotransmitter stimulation in the absence of PLP and GluR2 or when ␣v integrin levels were reduced. Chemotaxis assays of purified OPCs revealed that AMPA stimulation was neither attractive nor repulsive but clearly increased the migration rate of wild-type but not PLP null OPCs. AMPA receptor stimulation of wild-type OPCs caused decreased cell-surface expression of the GluR2 AMPA receptor subunit and increased intracellular Ca 2ϩ signaling, whereas PLP null OPCs did not reduce GluR2 at the cell surface or increase Ca 2ϩ signaling in response to AMPA treatment. Together, these studies demonstrate that PLP is critical for OPC responses to glutamate signaling and has important implications for OPC responses when levels of glutamate are high in the extracellular space, such as following demyelination.

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“…Activation of ISR, including PERK was reported to be critical in providing protection, 48 although the molecular mechanisms leading to inhibition of cell death were not clear. Unlike previous reports 9,32,33,48 suggesting that protection by IFNγ requires activation of the ISR, we did not observe phosphorylation of PERK and BiP expression induced by IFNγ. This suggests that the UPR was not activated in our system, and that there was no ER stress induced by IFNγ or TNFα.…”

Section: Discussionmentioning

confidence: 99%

cFLIP is critical for oligodendrocyte protection from inflammation

et al. 2015

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Neuroinflammation associated with degenerative central nervous system disease and injury frequently results in oligodendrocyte death. While promoting oligodendrocyte viability is a major therapeutic goal, little is known about protective signaling strategies. We report that in highly purified rat oligodendrocytes, interferon gamma (IFNγ) activates a signaling pathway that protects these cells from tumor necrosis factor alpha (TNFα)-induced cytotoxicity. IFNγ protection requires Jak (Janus kinase) activation, components of the integrated stress response and NF-κB activation. Although NF-κB activation also occurred transiently in the absence of IFNγ and presence of TNFα, this activation was not sufficient to prevent induction of the TNFα-responsive cell death pathway. Genetic inhibition of NF-κB translocation to the nucleus abrogated IFNγ-mediated protection and did not change the cell death induced by TNFα, suggesting that NF-κB activation via IFNγ induces a different set of responses than activation of NF-κB via TNFα. A promising candidate is the NF-κB target cFLIP (cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein), which is protease-deficient caspase homolog that inhibits caspase-3 activation. We show that IFNγ-mediated protection led to upregulation of cFLIP. Overexpression of cFLIP was sufficient for oligodendrocyte protection from TNFα and short hairpin RNA knockdown of cFLIP-abrogated IFNγ -mediated protection. To determine the relevance of our in vitro finding to the more complex in vivo situation, we determined the impact on oligodendrocyte death of regional cFLIP loss of function in a murine model of neuroinflammation. Our data show that downregulation of cFLIP during inflammation leads to death of oligodendrocytes and decrease of myelin in vivo. Taken together, we show that IFNγ-mediated induction of cFLIP expression provides a new mechanism by which this cytokine can protect oligodendrocytes from TNFα-induced cell death.

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Oligodendrocyte-Specific Activation of PERK Signaling Protects Mice against Experimental Autoimmune Encephalomyelitis

Cited by 101 publications

References 58 publications

Overexpression of CHOP in Myelinating Cells Does Not Confer a Significant Phenotype under Normal or Metabolic Stress Conditions

Overexpression of CHOP in Myelinating Cells Does Not Confer a Significant Phenotype under Normal or Metabolic Stress Conditions

Myelin Proteolipid Protein Complexes with v Integrin and AMPA Receptors In Vivo and Regulates AMPA-Dependent Oligodendrocyte Progenitor Cell Migration through the Modulation of Cell-Surface GluR2 Expression

cFLIP is critical for oligodendrocyte protection from inflammation

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