title: Role of copper and manganese in prion disease progression.
abstract: The cellular prion protein (PrP(C)), a copper binding protein has a primary role in the pathogenesis of in prion diseases. In these diseases alterations in the levels of copper and manganese have been described but how these alterations are involved in the pathogenesis is still unknown. Here we analysed synaptosomes of scrapie infected mice and observed a significant reduction in the amount of copper and an increase of the manganese content at day 100 after infection. Moreover a reduction of the copper content in mouse brains induced by application of copper poor diets was found to reduce the survival time of scrapie infected mice significantly, whereas enhanced administration of copper induced a significant delay in prion disease onset. Interestingly a significant higher amount of PrP(C) full length and misfolded PK-resistant PrP was observed in mice that were treated with an enhanced copper diet compared to controls. Moreover we could demonstrate that in healthy mock infected mice, a Cu(2+) rich/Mn(2+) poor diet induced a significantly decreased cleavage capability of PrP(C) compared to control mice. These new findings suggest that the copper content in mouse brains exerts an influence on the amount of PrP(C) and its cleavage properties and may affect the PrP conversion by depleted availability of functional PrP full length.
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Feodor-Lynen-Str. 23, D-81377 Munich, Germany.
authors.forename: Gerda
authors.initials: G
authors.lastname: Mitteregger
authors.forename: Stefan
authors.initials: S
authors.lastname: Korte
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shakarami
authors.forename: Jochen
authors.initials: J
authors.lastname: Herms
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kretzschmar
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D004032:Diet; D018450:Disease Progression; D005260:Female; D053208:Kaplan-Meier Estimate; D008345:Manganese / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018621:PrPC Proteins / Q000378:metabolism; D011328:Prions / Q000378:metabolism; D012608:Scrapie / Q000378:metabolism* / Q000401:mortality; D013574:Synaptosomes / Q000378:metabolism; D013997:Time Factors
chemical_list: D018621:PrPC Proteins; D011328:Prions; D008345:Manganese; D003300:Copper