title: Distribution of Misfolded Prion Protein Seeding Activity Alone Does Not Predict Regions of Neurodegeneration.
abstract: Protein misfolding is common across many neurodegenerative diseases, with misfolded proteins acting as seeds for "prion-like" conversion of normally folded protein to abnormal conformations. A central hypothesis is that misfolded protein accumulation, spread, and distribution are restricted to specific neuronal populations of the central nervous system and thus predict regions of neurodegeneration. We examined this hypothesis using a highly sensitive assay system for detection of misfolded protein seeds in a murine model of prion disease. Misfolded prion protein (PrP) seeds were observed widespread throughout the brain, accumulating in all brain regions examined irrespective of neurodegeneration. Importantly, neither time of exposure nor amount of misfolded protein seeds present determined regions of neurodegeneration. We further demonstrate two distinct microglia responses in prion-infected brains: a novel homeostatic response in all regions and an innate immune response restricted to sites of neurodegeneration. Therefore, accumulation of misfolded prion protein alone does not define targeting of neurodegeneration, which instead results only when misfolded prion protein accompanies a specific innate immune response.
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Alibhai
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Blanco
authors.affiliation: The National CJD Research and Surveillance Unit, Centre for Clinical Brain Sciences, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Barria
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Pedro
authors.initials: P
authors.lastname: Piccardo
authors.affiliation: Laboratory of Persistent Viral Diseases, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, United States of America.
authors.forename: Byron
authors.initials: B
authors.lastname: Caughey
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, United Kingdom.
authors.forename: V Hugh
authors.initials: VH
authors.lastname: Perry
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Tom C
authors.initials: TC
authors.lastname: Freeman
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Jean C
authors.initials: JC
authors.lastname: Manson
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D000072002:Prion Proteins / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000072002:Prion Proteins