Activation of endoplasmic reticulum stress signaling pathway is associated with neuronal degeneration in MoMuLV-ts1-induced spongiform encephalomyelopathy

Hun Taek Kim, Kara Waters, George Stoica, Wenan Qiang, Na Liu, Virginia L. Scofield, Paul K Y Wong

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Temperature-sensitive mutant of Moloney murine leukemia virus-TB (MoMuLV-ts1)-mediated neuronal death in mice is likely due to both loss of glial support and release of cytokines and neurotoxins from ts1-infected glial cells. Cytotoxic mediators present in ts1-induced spongiform lesions may generate endoplasmic reticulum (ER) stress, which has been implicated in the pathogenesis of a variety of neurodegenerative diseases. We investigated whether ER stress signaling is involved in ts1-mediated neuronal loss in the brain of infected mice. ts1-infected brainstems were found to show significant increases in phosphorylation of the double-stranded RNA-dependent protein kinase-like ER kinase and eukaryotic initiation factor 2-α. In addition, increased expression of growth arrest DNA damage 153 (GADD153), glucose-regulated protein 78, and caspase-12 were accompanied by increases in processing of caspase-12 and its downstream target, caspase-3. All of these events are markers of ER stress. We observed that GADD153 and cleaved caspase-3 were present in degenerative neurons in the lesions of infected mice, but not in uninfected controls. Phosphorylated calmodulin-dependent protein kinase II-α was significantly increased, and was coexpressed with GADD153 in a large proportion of neurons undergoing early and advanced degenerative changes. Finally, neuronal degeneration in spongiform lesions was associated with increase in calcium (Ca2+) accumulation in mitochondria. Together, these results suggest that ts1 infection-mediated neuronal degeneration in mice may result from activation of ER stress signaling pathways, presumably initiated by perturbation of Ca2+ homeostasis. Our findings highlight the importance of the ER stress signaling pathway in ts1 infection-induced neuronal degeneration and death.

Original languageEnglish (US)
Pages (from-to)816-827
Number of pages12
JournalLaboratory Investigation
Volume84
Issue number7
DOIs
StatePublished - Jul 2004
Externally publishedYes

Fingerprint

Endoplasmic Reticulum Stress
Caspase 12
DNA Damage
Neuroglia
Caspase 3
Growth
Eukaryotic Initiation Factor-2
eIF-2 Kinase
Moloney murine leukemia virus
Neurons
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Double-Stranded RNA
Neurotoxins
Infection
Endoplasmic Reticulum
Neurodegenerative Diseases
Brain Stem
Mitochondria
Homeostasis
Phosphotransferases

Keywords

  • Calcium
  • CaMKII-α
  • ER stress
  • GADD153
  • MoMuLV-ts1
  • Neuronal death
  • Spongiform encephalomyelopathy

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Activation of endoplasmic reticulum stress signaling pathway is associated with neuronal degeneration in MoMuLV-ts1-induced spongiform encephalomyelopathy. / Kim, Hun Taek; Waters, Kara; Stoica, George; Qiang, Wenan; Liu, Na; Scofield, Virginia L.; Wong, Paul K Y.

In: Laboratory Investigation, Vol. 84, No. 7, 07.2004, p. 816-827.

Research output: Contribution to journalArticle

Kim, Hun Taek ; Waters, Kara ; Stoica, George ; Qiang, Wenan ; Liu, Na ; Scofield, Virginia L. ; Wong, Paul K Y. / Activation of endoplasmic reticulum stress signaling pathway is associated with neuronal degeneration in MoMuLV-ts1-induced spongiform encephalomyelopathy. In: Laboratory Investigation. 2004 ; Vol. 84, No. 7. pp. 816-827.
@article{d46cd7d801114727b21b4a7b50f2b91e,
title = "Activation of endoplasmic reticulum stress signaling pathway is associated with neuronal degeneration in MoMuLV-ts1-induced spongiform encephalomyelopathy",
abstract = "Temperature-sensitive mutant of Moloney murine leukemia virus-TB (MoMuLV-ts1)-mediated neuronal death in mice is likely due to both loss of glial support and release of cytokines and neurotoxins from ts1-infected glial cells. Cytotoxic mediators present in ts1-induced spongiform lesions may generate endoplasmic reticulum (ER) stress, which has been implicated in the pathogenesis of a variety of neurodegenerative diseases. We investigated whether ER stress signaling is involved in ts1-mediated neuronal loss in the brain of infected mice. ts1-infected brainstems were found to show significant increases in phosphorylation of the double-stranded RNA-dependent protein kinase-like ER kinase and eukaryotic initiation factor 2-α. In addition, increased expression of growth arrest DNA damage 153 (GADD153), glucose-regulated protein 78, and caspase-12 were accompanied by increases in processing of caspase-12 and its downstream target, caspase-3. All of these events are markers of ER stress. We observed that GADD153 and cleaved caspase-3 were present in degenerative neurons in the lesions of infected mice, but not in uninfected controls. Phosphorylated calmodulin-dependent protein kinase II-α was significantly increased, and was coexpressed with GADD153 in a large proportion of neurons undergoing early and advanced degenerative changes. Finally, neuronal degeneration in spongiform lesions was associated with increase in calcium (Ca2+) accumulation in mitochondria. Together, these results suggest that ts1 infection-mediated neuronal degeneration in mice may result from activation of ER stress signaling pathways, presumably initiated by perturbation of Ca2+ homeostasis. Our findings highlight the importance of the ER stress signaling pathway in ts1 infection-induced neuronal degeneration and death.",
keywords = "Calcium, CaMKII-α, ER stress, GADD153, MoMuLV-ts1, Neuronal death, Spongiform encephalomyelopathy",
author = "Kim, {Hun Taek} and Kara Waters and George Stoica and Wenan Qiang and Na Liu and Scofield, {Virginia L.} and Wong, {Paul K Y}",
year = "2004",
month = "7",
doi = "10.1038/labinvest.3700104",
language = "English (US)",
volume = "84",
pages = "816--827",
journal = "Laboratory Investigation",
issn = "0023-6837",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - Activation of endoplasmic reticulum stress signaling pathway is associated with neuronal degeneration in MoMuLV-ts1-induced spongiform encephalomyelopathy

AU - Kim, Hun Taek

AU - Waters, Kara

AU - Stoica, George

AU - Qiang, Wenan

AU - Liu, Na

AU - Scofield, Virginia L.

AU - Wong, Paul K Y

PY - 2004/7

Y1 - 2004/7

N2 - Temperature-sensitive mutant of Moloney murine leukemia virus-TB (MoMuLV-ts1)-mediated neuronal death in mice is likely due to both loss of glial support and release of cytokines and neurotoxins from ts1-infected glial cells. Cytotoxic mediators present in ts1-induced spongiform lesions may generate endoplasmic reticulum (ER) stress, which has been implicated in the pathogenesis of a variety of neurodegenerative diseases. We investigated whether ER stress signaling is involved in ts1-mediated neuronal loss in the brain of infected mice. ts1-infected brainstems were found to show significant increases in phosphorylation of the double-stranded RNA-dependent protein kinase-like ER kinase and eukaryotic initiation factor 2-α. In addition, increased expression of growth arrest DNA damage 153 (GADD153), glucose-regulated protein 78, and caspase-12 were accompanied by increases in processing of caspase-12 and its downstream target, caspase-3. All of these events are markers of ER stress. We observed that GADD153 and cleaved caspase-3 were present in degenerative neurons in the lesions of infected mice, but not in uninfected controls. Phosphorylated calmodulin-dependent protein kinase II-α was significantly increased, and was coexpressed with GADD153 in a large proportion of neurons undergoing early and advanced degenerative changes. Finally, neuronal degeneration in spongiform lesions was associated with increase in calcium (Ca2+) accumulation in mitochondria. Together, these results suggest that ts1 infection-mediated neuronal degeneration in mice may result from activation of ER stress signaling pathways, presumably initiated by perturbation of Ca2+ homeostasis. Our findings highlight the importance of the ER stress signaling pathway in ts1 infection-induced neuronal degeneration and death.

AB - Temperature-sensitive mutant of Moloney murine leukemia virus-TB (MoMuLV-ts1)-mediated neuronal death in mice is likely due to both loss of glial support and release of cytokines and neurotoxins from ts1-infected glial cells. Cytotoxic mediators present in ts1-induced spongiform lesions may generate endoplasmic reticulum (ER) stress, which has been implicated in the pathogenesis of a variety of neurodegenerative diseases. We investigated whether ER stress signaling is involved in ts1-mediated neuronal loss in the brain of infected mice. ts1-infected brainstems were found to show significant increases in phosphorylation of the double-stranded RNA-dependent protein kinase-like ER kinase and eukaryotic initiation factor 2-α. In addition, increased expression of growth arrest DNA damage 153 (GADD153), glucose-regulated protein 78, and caspase-12 were accompanied by increases in processing of caspase-12 and its downstream target, caspase-3. All of these events are markers of ER stress. We observed that GADD153 and cleaved caspase-3 were present in degenerative neurons in the lesions of infected mice, but not in uninfected controls. Phosphorylated calmodulin-dependent protein kinase II-α was significantly increased, and was coexpressed with GADD153 in a large proportion of neurons undergoing early and advanced degenerative changes. Finally, neuronal degeneration in spongiform lesions was associated with increase in calcium (Ca2+) accumulation in mitochondria. Together, these results suggest that ts1 infection-mediated neuronal degeneration in mice may result from activation of ER stress signaling pathways, presumably initiated by perturbation of Ca2+ homeostasis. Our findings highlight the importance of the ER stress signaling pathway in ts1 infection-induced neuronal degeneration and death.

KW - Calcium

KW - CaMKII-α

KW - ER stress

KW - GADD153

KW - MoMuLV-ts1

KW - Neuronal death

KW - Spongiform encephalomyelopathy

UR - http://www.scopus.com/inward/record.url?scp=3042638296&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=3042638296&partnerID=8YFLogxK

U2 - 10.1038/labinvest.3700104

DO - 10.1038/labinvest.3700104

M3 - Article

C2 - 15094714

AN - SCOPUS:3042638296

VL - 84

SP - 816

EP - 827

JO - Laboratory Investigation

JF - Laboratory Investigation

SN - 0023-6837

IS - 7

ER -