Aggravation of ischemic brain injury by prion protein deficiency: role of ERK-1/-2 and STAT-1.
The cellular isoform of prion protein, PrPc, may confer neuroprotection in the brain, according to recent studies. To elucidate the role of PrPc in stroke pathology, we subjected PrPc-knockout (Prnp(0/0)), wild-type and PrPc-transgenic (tga20) mice to 30 min of intraluminal middle cerebral artery occlusion, followed by 3, 24 or 72 h reperfusion, and examined how PrPc levels influence brain injury and cell signaling. In immunohistochemical experiments and Western blots, we show that PrPc expression is absent in the brains of Prnp(0/0) mice, detectable in wild-type controls and approximately 4.0-fold elevated in tga20 mice. We provide evidence that PrPc deficiency increases infarct size by approximately 200%, while transgenic PrPc restores tissue viability, albeit not above levels in wild-type animals. To elucidate the mechanisms underlying Prnp(0/0)-induced injury, we performed Western blots, which revealed increased activities of ERK-1/-2, STAT-1 and caspase-3 in ischemic brains of Prnp(0/0)mice. Our data suggest a role of cytosolic signaling pathways in Prnp(0/0)-induced cell death.
Spudich
Annett
A
Department of Neurology, University Hospital Zurich, Frauenklinikstr. 26, CH-8091 Zürich, Switzerland.
Frigg
Rico
R
Kilic
Ertugrul
E
Kilic
Ulkan
U
Oesch
Bruno
B
Raeber
Alex
A
Bassetti
Claudio L
CL
Hermann
Dirk M
DM
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001929:Brain Edema / Q000235:genetics / Q000378:metabolism; D020520:Brain Infarction / Q000235:genetics / Q000378:metabolism*; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018621:PrPC Proteins / Q000235:genetics*; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D018621:PrPC Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases