Distribution of Misfolded Prion Protein Seeding Activity Alone Does Not Predict Regions of Neurodegeneration.

PLoS Biology. 2016;14(11):e1002579 DOI 10.1371/journal.pbio.1002579


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Journal Title: PLoS Biology

ISSN: 1544-9173 (Print); 1545-7885 (Online)

Publisher: Public Library of Science (PLoS)

LCC Subject Category: Science: Biology (General)

Country of publisher: United States

Language of fulltext: English

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James Alibhai
Richard A Blanco
Marcelo A Barria
Pedro Piccardo
Byron Caughey
V Hugh Perry
Tom C Freeman
Jean C Manson


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Time From Submission to Publication: 28 weeks


Abstract | Full Text

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.