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
Current Pharmaceutical Design
Title: Role of Copper in Prion Diseases: Deleterious or Beneficial?
Volume: 12 Issue: 20
Author(s): Lorena Varela-Nallar, Alfonso Gonzalez and Nibaldo C. Inestrosa
Affiliation:
Keywords: Prion protein, copper, misfolding, trafficking
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.
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Cite this article as:
Varela-Nallar Lorena, Gonzalez Alfonso and Inestrosa C. Nibaldo, Role of Copper in Prion Diseases: Deleterious or Beneficial?, Current Pharmaceutical Design 2006; 12 (20) . https://dx.doi.org/10.2174/138161206777698873
DOI https://dx.doi.org/10.2174/138161206777698873 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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