Gingerol prevents prion protein-mediated neuronal toxicity by regulating HIF prolyl hydroxylase 2 and prion protein

摘要

Prion diseases are a family of progressive neurodegenerative disorders, which are fatal in the majority of cases and affect both humans and domestic animals. Prion protein (PrP)?(106-126) retains the neurotoxic properties of the entire pathological PrPsc and it is generally used as a reasonable model to study the mechanisms responsible for prion diseases. In our previous studies, we demonstrated that hypoxia-inducible factor (HIF)-1α is involved in the gingerol-mediated protection of neuronal cells. HIF mediates cellular adaptations to low oxygen. Prolyl hydroxylase domain-containing protein?2 (PHD2) is an oxygen sensor that hydroxylates the HIF-α-subunit, promoting its proteasomal degradation under normoxic conditions. Thus, in the present study we wished to determine whether gingerol inhibits the catalytic activity of PHD2 and prevents HIF-1α protein proteasomal degradation, thereby preventing the occurrence of PrP?(106-126)-induced neuronal apoptosis. We used the pharmacological inhibition of PHD2 by dimethyloxalylglycine (DMOG) or deferoxamine (DFO) and the genetic inhibition of HIF-1α by HIF-1α small interfering RNA (siRNA) to block the effects of gingerol against PrP?(106-126)-induced neurotoxicity. Our results demonstrated that gingerol prevented PrP?(106?126)-induced neuronal apoptosis by upregulating HIF-1α and inhibiting the catalytic activity of PHD2 under normoxic conditions. Moreover, the protective effects of gingerol against PrP?(106-126)-induced neuronal apoptosis were associated with the upregulation of the expression of cellular prion protein (PrPc). In conclusion, our results indicate that gingerol has therapeutic potential for use in the treatment or prevention of prion diseases, and its inhibitory effects on the catalytic activity of PHD2 may be of clinical benefit.