Transgenic Fatal Familial Insomnia Mice Indicate Prion Infectivity-Independent Mechanisms of Pathogenesis and Phenotypic Expression of Disease

PLoS Pathogens

Cinzia Bisighini¹  Fabrizio Tagliavini¹  Natalia Fernández-Borges²  Joaquín Castilla²  Roberto Chiesa³  Federico Del Gallo³  Francesca Baracchi³  Laura Tapella⁴  Susanna Mantovani⁴  Claudia Balducci⁴  Liliana Comerio⁴  Alessandra Paladini⁴  Ihssane Bouybayoune⁴  Ilaria Bertani⁴  Elena Restelli⁴  Gianluigi Forloni⁴  Edoardo Micotti⁴  Luca Imeri⁵  Michela Mangieri⁵  Galina V. Beznoussenko⁶  Fabio Fiordaliso⁷ 

[1] Bio-Imaging Unit, Department of Cardiovascular Research, IRCCS—“Mario Negri” Institute for Pharmacological Research, Milan, Italy;CIC bioGUNE, Parque Tecnológico de Bizkaia, Derio, Spain;Department of Health Sciences, University of Milan Medical School, Milan, Italy;Department of Neuroscience, IRCCS—“Mario Negri” Institute for Pharmacological Research, Milan, Italy;Division of Neuropathology and Neurology, IRCCS Foundation “Carlo Besta” National Neurological Institute, Milan, Italy;IFOM—FIRC Institute of Molecular Oncology, Milan, Italy;IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

关键词: Sleep;    Mouse models;    Fatal familial insomnia;    Mice;    Electroencephalography;    Neurons;    Animal prion diseases;    Prion diseases;   

DOI  :  10.1371/journal.ppat.1004796

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY