Transgenic fatal familial insomnia mice indicate prion infectivity-independent mechanisms of pathogenesis and phenotypic expression of disease
Fatal familial insomnia (FFI) and a genetic form of Creutzfeldt-Jakob disease (CJD178) are clinically different prion disorders linked to the D178N prion protein (PrP) mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N...
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Published in | PLoS pathogens Vol. 11; no. 4; p. e1004796 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Public Library of Science
01.04.2015
Public Library of Science (PLoS) |
Subjects | |
Online Access | Get full text |
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Summary: | Fatal familial insomnia (FFI) and a genetic form of Creutzfeldt-Jakob disease (CJD178) are clinically different prion disorders linked to the D178N prion protein (PrP) mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N PrP misfolding, leading to the formation of distinctive prion strains with specific neurotoxic properties. However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known. We generated transgenic (Tg) mice expressing the mouse PrP homolog of the FFI mutation. These mice synthesize a misfolded form of mutant PrP in their brains and develop a neurological illness with severe sleep disruption, highly reminiscent of FFI and different from that of analogously generated Tg(CJD) mice modeling CJD178. No prion infectivity was detectable in Tg(FFI) and Tg(CJD) brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation. Tg(FFI) and Tg(CJD) neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype. |
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Bibliography: | Conceived and designed the experiments: JC FT LI RC. Performed the experiments: IBo SM FDG IBe ER LC LT FB NFB MM CB GVB AP CB EM FF. Analyzed the data: IBo SM FDG IBe ER LC LT FB NFB MM CB GVB AP CB EM GF JC FF FT LI RC. Wrote the paper: FT LI RC. These authors share first authorship on this work. Present address: Department of Neurological and Movement Sciences, University of Verona, Verona, Italy Present address: Department of Neuropathology, Golgi Cenci Foundation, Abbiategrasso (MI), Italy Present address: School of Biomedical Sciences, The University of Queensland, Brisbane, Australia The authors have declared that no competing interests exist. |
ISSN: | 1553-7374 1553-7366 1553-7374 |
DOI: | 10.1371/journal.ppat.1004796 |