Role of Copper in Prion Diseases: Deleterious or Beneficial?

Lorena      Varela-Nallar; Alfonso      Gonzalez; Nibaldo   C.   Inestrosa

doi:10.2174/138161206777698873

Abstract

Prion diseases are fatal neurodegenerative disorders associated with conformational conversion of the cellular prion protein (PrPC) into an isoform designated PrPSc. The pathogenic mechanism that links this conformational distortion with the development of prion diseases is unknown. PrPC is a GPI-anchored cell surface protein that associates with lipid rafts, undergoes endocytosis and recycles. Although the physiological function of PrPC remains unknown it has been related with a number of processes, including cellular copper transport and metabolism. PrPC has two copper binding domains and copper induces changes in PrPC conformation and endocytic behavior. However, the role of copper in prion diseases is unclear. PrPC expression and interaction with PrPSc are required for prion progression. Therefore, factors that modify PrPC expression levels, conformation, intracellular trafficking and segregation into membranous microdomains could change the opportunities for and the quality of PrPC interactions with PrPSc and thus influence prion pathogenesis. Here we discuss the potential of copper as modifier of these processes, attempting to integrate apparently contradictory observations which so far left uncertain whether copper exerts beneficial or detrimental effects upon prion diseases. The outcome of copper effects might be the resultant of two opposite conditions: one promoting misfolding of PrPC leading to prion conversion and the other promoting PrPC trafficking through pathways that prevent PrPSc-PrPC interaction. Which of these predominates might vary under distinct conditions that need to be defined before deciding on the feasibility of either incorporating or avoiding metal influences in prion disease therapies.

Keywords: Prion protein, copper, misfolding, trafficking

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