Endoplasmic reticulum stress in disorders of myelinating cells

Lin, Wensheng; Popko, Brian

doi:10.1038/nn.2273

Cited by 231 publications

(234 citation statements)

References 91 publications

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“…Syncytin-1 was found to be more highly expressed in the glial cells of MS lesions, specifically in astrocytes and microglia (28). Moreover, Syncytin-1 has been shown to induce ER stress in astrocytes (23), in keeping with the observations from other groups suggesting ER stress is involved in MS-related disease mechanisms (29)(30)(31).…”

supporting

confidence: 81%

Neuroinflammation and Endoplasmic Reticulum Stress Are Coregulated by Crocin To Prevent Demyelination and Neurodegeneration

Deslauriers

Afkhami-Goli

Paul

et al. 2011

The Journal of Immunology

113

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Endoplasmic reticulum (ER) stress is a homeostatic mechanism, which is used by cells to adapt to intercellular and intracellular changes. Moreover, ER stress is closely linked to inflammatory pathways. We hypothesized that ER stress is an integral component of neuroinflammation and contributes to the development of neurological diseases. In autopsied brain specimens from multiple sclerosis (MS) and non-MS patients, XBP-1 spliced variant (XBP-1/s) was increased in MS brains (p < 0.05) and was correlated with the expression of the human endogenous retrovirus-W envelope transcript, which encodes the glycoprotein, Syncytin-1 (p < 0.05). In primary human fetal astrocytes transfected with a Syncytin-1–expressing plasmid, XBP-1/s, BiP, and NOS2 were induced, which was suppressed by crocin treatment (p < 0.05). Crocin also protected oligodendrocytes exposed to cytotoxic supernatants derived from Syncytin-1–expressing astrocytes (p < 0.05) and NO-mediated oligodendrocytotoxicity (p < 0.05). During experimental autoimmune encephalomyelitis (EAE), the transcript levels of the ER stress genes XBP-1/s, BiP, PERK, and CHOP were increased in diseased spinal cords compared with healthy littermates (p < 0.05), although CHOP expression was not involved in the EAE disease phenotype. Daily treatment with crocin starting on day 7 post-EAE induction suppressed ER stress and inflammatory gene expression in spinal cords (p < 0.05), which was accompanied by preserved myelination and axonal density, together with reduced T cell infiltration and macrophage activation. EAE-associated neurobehavioral deficits were also ameliorated by crocin treatment (p < 0.05). These findings underscored the convergent roles of pathogenic ER stress and immune pathways in neuroinflammatory disease and point to potential therapeutic applications for crocin.

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supporting

confidence: 81%

Neuroinflammation and Endoplasmic Reticulum Stress Are Coregulated by Crocin To Prevent Demyelination and Neurodegeneration

Deslauriers

Afkhami-Goli

Paul

et al. 2011

The Journal of Immunology

113

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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: Discussioncontrasting

confidence: 99%

“…In contrast with effects of IFNγ on PKR activation, we found no activation of PKR-like endoplasmic reticulum (ER) kinase (PERK), which was recently implicated in IFNγ-mediated protection of oligodendrocytes 9,32,33 ( Figure 4a). Furthermore, we found no change in expression of the ER chaperone protein BiP (Figure 4e), which is associated with accumulation Figure 1 IFNγ protects GalC + oligodendrocytes from TNFα-induced cell death and inhibits caspase activation.…”

Section: Resultsmentioning

confidence: 58%

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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“…Reduced acetyl CoA availability due to aspartoacylase deficiency could negatively impact protein folding and stabilization, targeting proteins for degradation. Oligodendrocytes are highly susceptible to ER stress associated with disruptions in protein synthesis and trafficking (Lin 2009). In the ASPAKO mouse, a severe loss of myelin basic protein and PLP/DM20 proteolipid proteins has been observed, combined with a decrease in myelinated fibers (Kumar et al 2009).…”

Section: Deficiency Of Aspa-derived Acetate Compromises Oligodendrocymentioning

confidence: 99%

Endoplasmic reticulum stress in disorders of myelinating cells

Cited by 231 publications

References 91 publications

Neuroinflammation and Endoplasmic Reticulum Stress Are Coregulated by Crocin To Prevent Demyelination and Neurodegeneration

Neuroinflammation and Endoplasmic Reticulum Stress Are Coregulated by Crocin To Prevent Demyelination and Neurodegeneration

cFLIP is critical for oligodendrocyte protection from inflammation

Making the White Matter Matters: Progress in Understanding Canavan’s Disease and Therapeutic Interventions Through Eight Decades

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