Abstract:
:Prion diseases are fatal neurodegenerative disorders associated with conformational conversion of the cellular prion protein (PrP(C)) into an isoform designated PrP(Sc). The pathogenic mechanism that links this conformational distortion with the development of prion diseases is unknown. PrP(C) is a GPI-anchored cell surface protein that associates with lipid rafts, undergoes endocytosis and recycles. Although the physiological function of PrP(C) remains unknown it has been related with a number of processes, including cellular copper transport and metabolism. PrP(C) has two copper binding domains and copper induces changes in PrP(C) conformation and endocytic behavior. However, the role of copper in prion diseases is unclear. PrP(C) expression and interaction with PrP(Sc) are required for prion progression. Therefore, factors that modify PrP(C) expression levels, conformation, intracellular trafficking and segregation into membranous microdomains could change the opportunities for and the quality of PrP(C) interactions with PrP(Sc) 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 PrP(C) leading to prion conversion and the other promoting PrP(C) trafficking through pathways that prevent PrP(Sc)-PrP(C) 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.
journal_name
Curr Pharm Desjournal_title
Current pharmaceutical designauthors
Varela-Nallar L,González A,Inestrosa NCdoi
10.2174/138161206777698873subject
Has Abstractpub_date
2006-01-01 00:00:00pages
2587-95issue
20eissn
1381-6128issn
1873-4286journal_volume
12pub_type
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journal_title:Current pharmaceutical design
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更新日期:2005-01-01 00:00:00
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journal_title:Current pharmaceutical design
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更新日期:2013-01-01 00:00:00
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