Regulation of prion protein gene expression by heavy metals

Abstract

Prion diseases are a family of neurodegenerative disorders characterized by neuronal cell death and gliosis. Despite its pathological relevance, the normal function of the prion protein (PrPc) is still unknown. Due to the ability of PrPc to bind and reduce copper it has been suggested that it could be involved in copper homeostasis. Since this metal regulates gene expression of copper‐related proteins, the objective of this work was to learn whether this metal regulates PrPc gene expression. With this purpose in mind, we used PC12 and C6 clones stably transfected with a reporter vector that contains the luciferase gene under control of the PrPc promoter. We observed that copper treatment increases PrPc promoter activity in all PC12 clones in a dose dependent manner, however, this effect was not observed for any of the C6 clones. We also evaluated the effect of other heavy metals on PrPc promoter activity and found that cadmium increases luciferase activity on PC12 clones but not on C6 clones, and zinc has no effect on any of the clones studied. These results show that there is an up‐regulation of PrPc gene expression by copper and cadmium and suggest that this regulation might be tissue specific. This up‐regulation may involve a metal‐responsive element (MRE) located on the PrPc promoter. Supported by CIMM‐ICA, FONDAP‐Biomedicine No. 13980001 and Millennium Institute (MIFAB) No. 2398969.