Role of copper in prion diseases: Deleterious or beneficial?

Lorena Varela-Nallar, Alfonso González, Nibaldo C. Inestrosa

Resultado de la investigación: Review article

17 Citas (Scopus)

Resumen

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.

Idioma originalEnglish
Páginas (desde-hasta)2587-2595
Número de páginas9
PublicaciónCurrent Pharmaceutical Design
Volumen12
N.º20
DOI
EstadoPublished - jul 2006

Huella dactilar

Prion Diseases
Copper
Prions
Endocytosis
Neurodegenerative Diseases
Protein Isoforms
Membrane Proteins
Metals
Lipids

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Pharmacology
  • Drug Discovery

Citar esto

Varela-Nallar, Lorena ; González, Alfonso ; Inestrosa, Nibaldo C. / Role of copper in prion diseases : Deleterious or beneficial?. En: Current Pharmaceutical Design. 2006 ; Vol. 12, N.º 20. pp. 2587-2595.
@article{9ec15b01382d489faef0e2e52f552dee,
title = "Role of copper in prion diseases: Deleterious or beneficial?",
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 = "Copper, Misfolding, Prion protein, Trafficking",
author = "Lorena Varela-Nallar and Alfonso Gonz{\'a}lez and Inestrosa, {Nibaldo C.}",
year = "2006",
month = "7",
doi = "10.2174/138161206777698873",
language = "English",
volume = "12",
pages = "2587--2595",
journal = "Current Pharmaceutical Design",
issn = "1381-6128",
publisher = "Bentham Science Publishers B.V.",
number = "20",

}

Role of copper in prion diseases : Deleterious or beneficial? / Varela-Nallar, Lorena; González, Alfonso; Inestrosa, Nibaldo C.

En: Current Pharmaceutical Design, Vol. 12, N.º 20, 07.2006, p. 2587-2595.

Resultado de la investigación: Review article

TY - JOUR

T1 - Role of copper in prion diseases

T2 - Deleterious or beneficial?

AU - Varela-Nallar, Lorena

AU - González, Alfonso

AU - Inestrosa, Nibaldo C.

PY - 2006/7

Y1 - 2006/7

N2 - 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.

AB - 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.

KW - Copper

KW - Misfolding

KW - Prion protein

KW - Trafficking

UR - http://www.scopus.com/inward/record.url?scp=33745761652&partnerID=8YFLogxK

U2 - 10.2174/138161206777698873

DO - 10.2174/138161206777698873

M3 - Review article

C2 - 16842180

AN - SCOPUS:33745761652

VL - 12

SP - 2587

EP - 2595

JO - Current Pharmaceutical Design

JF - Current Pharmaceutical Design

SN - 1381-6128

IS - 20

ER -