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 language | English (US) |
|---|---|
| Pages (from-to) | 816-827 |
| Number of pages | 12 |
| Journal | Laboratory Investigation |
| Volume | 84 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2004 |
| Externally published | Yes |
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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 journal › Article
}
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 -