Humanin rescues cortical neurons from prion-peptide-induced apoptosis.

We recently demonstrated that a soluble oligomeric prion peptide, the putative 118-135 transmembrane domain of prion protein (PrP), exhibited membrane fusogenic properties and induced apoptotic cell death both in vitro and in vivo. A recently discovered rescue factor humanin (HN) was shown to protect neuronal cells from various insults involved in human neurodegenerative diseases. We thus addressed the question of whether HN might modulate the apoptosis induced by the soluble PrP(118-135) fragment. We found that the incubation of rat cortical neurons with 10 microM HN prevented soluble PrP(118-135) fragment-induced cell death concomitantly with inhibition of apoptotic events. An HN variant, termed HNG, exhibited a 500-fold increase in the protective activity in cortical neurons, whereas the HNA variant displayed no protective effect. The effects of HN and HNG peptides did not require a preincubation with the PrP(118-135) fragment, strongly suggesting that these peptides rescue cells independently of a direct interaction with the prion peptide. By contrast, and in agreement with a previous study, HN had no effect on the fibrillar PrP(106-126) peptide-induced cell death. This protective effect for neurons from PrP(118-135)-induced cell death strongly suggests that PrP(118-135) and PrP(106-126) peptides may trigger different pathways leading to neuronal apoptosis.