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

Owen M. Siggs, Justin T. Cruite, Xin Du, Sophie Rutschmann, Eliezer Masliah, Bruce Beutler, Michael B A Oldstone

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)13733-13738
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number34
StatePublished - Aug 21 2012


  • ATPase
  • Menkes disease
  • N-ethyl-N-nitrosourea (ENU) mutagenesis
  • Neurodegeneration
  • Pigmentation

ASJC Scopus subject areas

  • General


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