Dataset Information

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-?, 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.

SUBMITTER: Lin Y

PROVIDER: S-EPMC3906495 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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PERK activation preserves the viability and function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases.

Lin Yifeng Y Huang Guangcun G Jamison Stephanie S Li Jin J Harding Heather P HP Ron David D Lin Wensheng W

The American journal of pathology 20131119 2

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 remyelinati ...[more]

PMID: 24269558

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Project description:Cognitive deficits occur in over half of multiple sclerosis patients, with hippocampal-dependent learning and memory commonly impaired. Data from in vivo MRI and post-mortem studies in MS indicate that the hippocampus is targeted. However, the relationship between structural pathology and dysfunction of the hippocampus in MS remains unclear. Hippocampal neuropathology also occurs in experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. Although estrogen treatment of EAE has been shown to be anti-inflammatory and neuroprotective in the spinal cord, it is unknown if estrogen treatment may prevent hippocampal pathology and dysfunction. In the current study we examined excitatory synaptic transmission during EAE and focused on pathological changes in synaptic protein complexes known to orchestrate functional synaptic transmission in the hippocampus. We then determined if estriol, a candidate hormone treatment, was capable of preventing functional changes in synaptic transmission and corresponding hippocampal synaptic pathology. Electrophysiological studies revealed altered excitatory synaptic transmission and paired-pulse facilitation (PPF) during EAE. Neuropathological experiments demonstrated that there were decreased levels of pre- and post-synaptic proteins in the hippocampus, diffuse loss of myelin staining and atrophy of the pyramidal layers of hippocampal cornu ammonis 1 (CA1). Estriol treatment prevented decreases in excitatory synaptic transmission and lessened the effect of EAE on PPF. In addition, estriol treatment prevented several neuropathological alterations that occurred in the hippocampus during EAE. Cross-modality correlations revealed that deficits in excitatory synaptic transmission were significantly correlated with reductions in trans-synaptic protein binding partners known to modulate excitatory synaptic transmission. To our knowledge, this is the first report describing a functional correlate to hippocampal neuropathology in any MS model. Furthermore, a treatment was identified that prevented both deficits in synaptic function and hippocampal neuropathology.

Dataset Information

PERK activation preserves the viability and function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases.

Publications

PERK activation preserves the viability and function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases.

Similar Datasets

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