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Proc Natl Acad Sci U S A. 2012 Aug 21;109(34):13733-8. doi: 10.1073/pnas.1211499109. Epub 2012 Aug 6.

Disruption of copper homeostasis due to a mutation of Atp7a delays the onset of prion disease.

Author information

1
Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.

Abstract

Copper influences the pathogenesis of prion disease, but whether it is beneficial or detrimental remains controversial. Copper homeostasis is also essential for normal physiology, as highlighted by the spectrum of diseases caused by disruption of the copper transporting enzymes ATP7A and ATP7B. Here, by using a forward genetics approach in mice, we describe the isolation of three alleles of Atp7a, each with different phenotypic consequences. The mildest of the three, Atp7a(brown), was insufficient to cause lethality in hemizygotes or mottling of the coat in heterozygotes, but did lead to coat hypopigmentation and reduced copper content in the brains of hemizygous males. When challenged with Rocky Mountain Laboratory scrapie, the onset of prion disease was delayed in Atp7a(brown) mice, and significantly less proteinase-resistant prion protein was found in the brains of moribund Atp7a(brown) mice compared with WT littermates. Our results establish that ATP7A-mediated copper homeostasis is important for the formation of pathogenic proteinase-resistant prion protein.

PMID:
22869751
PMCID:
PMC3427069
DOI:
10.1073/pnas.1211499109
[Indexed for MEDLINE]
Free PMC Article

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