Activation of endoplasmic reticulum stress signaling pathway is associated with neuronal degeneration in MoMuLV-ts1-induced spongiform encephalomyelopathy.
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-alpha. 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-alpha 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 (Ca(2+)) 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 Ca(2+) homeostasis. Our findings highlight the importance of the ER stress signaling pathway in ts1 infection-induced neuronal degeneration and death.
Kim
Hun-Taek
HT
Department of Pathobiology, Texas A&M University, College Station, TX 77843, USA.
Waters
Kara
K
Stoica
George
G
Qiang
Wenan
W
Liu
Na
N
Scofield
Virginia L
VL
Wong
Paul K Y
PK
D000818:Animals; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000502:physiology; D002493:Central Nervous System Diseases / Q000378:metabolism* / Q000473:pathology*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005786:Gene Expression Regulation; D051379:Mice; D008979:Moloney murine leukemia virus; D009410:Nerve Degeneration / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics
D022762:CCAAT-Enhancer-Binding Proteins; C497250:Ddit3 protein, mouse; D014157:Transcription Factors; D051742:Transcription Factor CHOP; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517671:Camk2a protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D002118:Calcium