TY - JOUR
T1 - Disruption of copper homeostasis due to a mutation of Atp7a delays the onset of prion disease
AU - Siggs, Owen M.
AU - Cruite, Justin T.
AU - Du, Xin
AU - Rutschmann, Sophie
AU - Masliah, Eliezer
AU - Beutler, Bruce
AU - Oldstone, Michael B A
PY - 2012/8/21
Y1 - 2012/8/21
N2 - 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.
AB - 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.
KW - ATPase
KW - Menkes disease
KW - N-ethyl-N-nitrosourea (ENU) mutagenesis
KW - Neurodegeneration
KW - Pigmentation
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U2 - 10.1073/pnas.1211499109
DO - 10.1073/pnas.1211499109
M3 - Article
C2 - 22869751
AN - SCOPUS:84865287014
SN - 0027-8424
VL - 109
SP - 13733
EP - 13738
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 34
ER -