Short Communication: Spinal Cord Trauma Activates Processing of xbp1 mRNA Indicative of Endoplasmic Reticulum Dysfunction

Aufenberg, Christoph; Wenkel, Simone; Mautes, A.; Paschen, Wulf

doi:10.1089/neu.2005.22.1018

Cited by 24 publications

(18 citation statements)

References 20 publications

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“…Accumulating evidence suggests that ER stress is particularly relevant to a variety of neurological disorders involving the misfolding and deposition of abnormal protein aggregates in the brain. Engagement of the IRE1␣-XBP-1 pathway occurs in animal models of brain ischemia injury (16,17), brain trauma (18), behavioral stress (19), retinal cell death (20), spinal cord injury (21) and trauma (22), and brain viral infections (23). Moreover, the accumulation of mutant protein aggregates in cellular and animal models of Huntington's disease (24), Parkinson's disease (25), and ALS (26,27) correlates with IRE1␣ activation, suggesting that the UPR is a primary response against neurodegeneration.…”

mentioning

confidence: 99%

Unfolded protein response transcription factor XBP-1 does not influence prion replication or pathogenesis

Hetz

Lee

Gonzalez-Romero

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

143

130

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The unfolded protein response (UPR) is a conserved adaptive reaction that increases cell survival under endoplasmic reticulum (ER) stress conditions. X-box-binding protein-1 (XBP-1) is a key transcriptional regulator of the UPR that activates genes involved in protein folding, secretion, and degradation to restore ER function. The occurrence of chronic ER stress has been extensively described in neurodegenerative conditions linked to protein misfolding and aggregation. However, the role of the UPR in the CNS has not been addressed directly. Here we describe the generation of a brain-specific XBP-1 conditional KO strain (XBP-1 Nes−/− ). XBP-1 Nes−/− mice are viable and do not develop any spontaneous neurological dysfunction, although ER stress signaling in XBP-1 Nes−/− primary neuronal cell cultures was impaired. To assess the function of XBP-1 in pathological conditions involving protein misfolding and ER stress, we infected XBP-1 Nes−/− mice with murine prions. To our surprise, the activation of stress responses triggered by prion replication was not influenced by XBP-1 deficiency. Neither prion aggregation, neuronal loss, nor animal survival was affected. Hence, this most highly conserved arm of the UPR may not contribute to the occurrence or pathology of neurodegenerative conditions associated with prion protein misfolding despite predictions that such diseases are related to ER stress and irreversible neuronal damage.

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mentioning

confidence: 99%

Unfolded protein response transcription factor XBP-1 does not influence prion replication or pathogenesis

Hetz

Lee

Gonzalez-Romero

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

143

130

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“…Aggregated amyloid beta peptide (implicated in Alzheimer's disease) triggers ER stress in vivo when injected into the brain of healthy animals [79,80]. In addition, in many other conditions of neuronal dysfunction, such as brain trauma and ischemia, the involvement of the UPR/ER stress pathway has been implicated [81]. Finally, mice homozygous for the woozy mutation develop adult-onset ataxia with cerebellar Purkinje cell loss [82].…”

Section: Discussionmentioning

confidence: 99%

Stressing Out the ER: A Role of the Unfolded Protein Response in Prion-Related Disorders

Hetz¹,

Soto²

2006

CMM

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Transmissible Spongiform Encephalopathies are fatal and infectious neurodegenerative diseases characterized by extensive neuronal apoptosis and the accumulation of an abnormally folded form of the cellular prion protein (PrP), denoted PrP SC . Compelling evidence suggests the involvement of several signaling pathways in prion pathogenesis, including proteasome dysfunction, alterations in the protein maturation pathways and the unfolded protein response. Recent reports indicate that endoplasmic reticulum stress due to the PrP misfolding may be a critical factor mediating neuronal dysfunction in prion diseases. These findings have applications for developing novel strategies for treatment and early diagnosis of transmissible spongiform encephalopathies and other neurodegenerative diseases.

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“…Recent studies indicate that ER stress is an early tissue reaction after SCI in different models, including mechanical trauma and hypoxia. 8,[10][11][12][13]27 Here we show a fast activation of a range of UPR responses after SCI, including the expression of the proximal components ATF4 and XBP1, major transcription factors governing this pathway, in addition to the upregulation of downstream target genes. Remarkably, UPR activation was also observed in regions distant from the primary injury zone, suggesting the activation of a broad ER stress response in the spinal cord after damage.…”

Section: Discussionmentioning

confidence: 70%

“…3 Correlative studies indicate that markers of ER stress are observed in different models of SCI triggered by trauma (by contusion and hemisection) and ischemia. [8][9][10][11][12] Using a contusion model, ER stress responses were observed in the damaged zone, including XBP1 mRNA splicing, in addition to the induction of CHOP and the ER chaperone BiP. 10 Neuronal cells presented a fast and transient activation of UPR markers, whereas oligodendrocytes and astroglia showed sustained activation for several days.…”

mentioning

confidence: 99%

Activation of the Unfolded Protein Response Enhances Motor Recovery after Spinal Cord Injury

et al. 2013

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Spinal cord injury (SCI) is a major cause of paralysis, and involves multiple cellular and tissular responses including demyelination, inflammation, cell death and axonal degeneration. Recent evidence suggests that perturbation on the homeostasis of the endoplasmic reticulum (ER) is observed in different SCI models; however, the functional contribution of this pathway to this pathology is not known. Here we demonstrate that SCI triggers a fast ER stress reaction (1-3 h) involving the upregulation of key components of the unfolded protein response (UPR), a process that propagates through the spinal cord. Ablation of X-box-binding protein 1 (XBP1) or activating transcription factor 4 (ATF4) expression, two major UPR transcription factors, leads to a reduced locomotor recovery after experimental SCI. The effects of UPR inactivation were associated with a significant increase in the number of damaged axons and reduced amount of oligodendrocytes surrounding the injury zone. In addition, altered microglial activation and pro-inflammatory cytokine expression were observed in ATF4 deficient mice after SCI. Local expression of active XBP1 into the spinal cord using adeno-associated viruses enhanced locomotor recovery after SCI, and was associated with an increased number of oligodendrocytes. Altogether, our results demonstrate a functional role of the UPR in SCI, offering novel therapeutic targets to treat this invalidating condition.

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Short Communication: Spinal Cord Trauma Activates Processing of xbp1 mRNA Indicative of Endoplasmic Reticulum Dysfunction

Cited by 24 publications

References 20 publications

Unfolded protein response transcription factor XBP-1 does not influence prion replication or pathogenesis

Unfolded protein response transcription factor XBP-1 does not influence prion replication or pathogenesis

Stressing Out the ER: A Role of the Unfolded Protein Response in Prion-Related Disorders

Activation of the Unfolded Protein Response Enhances Motor Recovery after Spinal Cord Injury

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