期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 34, 页码 13733-13738出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1211499109
关键词
neurodegeneration; N-ethyl-N-nitrosourea (ENU) mutagenesis; Menkes disease; ATPase; pigmentation
资金
- National Institute of Allergy and Infectious Diseases/National Institutes of Health [HHSN272200700038C, AG04342, AG18440, AG022074, NS057096]
- General Sir John Monash Foundation
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.
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