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 (Prnp0/0), 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 Prnp0/0 mice, detectable in wild-type controls and ∼4.0-fold elevated in tga20 mice. We provide evidence that PrPc deficiency increases infarct size by ∼200%, while transgenic PrPc restores tissue viability, albeit not above levels in wild-type animals. To elucidate the mechanisms underlying Prnp0/0-induced injury, we performed Western blots, which revealed increased activities of ERK-1/-2, STAT-1 and caspase-3 in ischemic brains of Prnp0/0 mice. Our data suggest a role of cytosolic signaling pathways in Prnp0/0-induced cell death.