NR ATXN
AU Spudich,A.; Frigg,R.; Kilic,E.; Kilic,U.; Oesch,B.; Raeber,A.; Bassetti,C.L.; Hermann,D.M.
TI Aggravation of ischemic brain injury by prion protein deficiency: role of ERK-1/-2 and STAT-1.
QU Neurobiology of Disease 2005 Nov; 20(2): 442-9
PT journal article
AB 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.
MH Animals; Apoptosis/genetics; Brain Edema/genetics/metabolism; Brain Infarction/genetics/*metabolism; Brain Ischemia/genetics/*metabolism; Caspases/metabolism; Cell Survival/genetics; Extracellular Signal-Regulated MAP Kinases/*metabolism; Infarction, Middle Cerebral Artery/genetics/metabolism; JNK Mitogen-Activated Protein Kinases/genetics/metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; PrPc Proteins/*genetics; Reperfusion Injury/genetics/metabolism; Research Support, Non-U.S. Gov't; STAT1 Transcription Factor/*metabolism; Signal Transduction/genetics; Up-Regulation/genetics
AD Department of Neurology, University Hospital Zürich, Frauenklinikstr. 26, CH-8091 Zürich, Switzerland.
SP englisch
PO USA