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Distribution of misfolded prion protein seeding activity alone does not predict regions of neurodegeneration

Distribution of misfolded prion protein seeding activity alone does not predict regions of neurodegeneration
Distribution of misfolded prion protein seeding activity alone does not predict regions of neurodegeneration
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 is 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 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 11 novel homeostatic response in all regions and an innate immune response restricted to sites of 12 neurodegeneration. Therefore accumulation of misfolded prion protein alone does not define targeting 13 of neurodegeneration which instead results only when misfolded prion protein accompanies a specific 14 innate immune response.
1544-9173
Alibhai, James
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Blanco, Richard A.
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Barria, Pedro Piccardo
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Caughey, Byron
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Perry, Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4
Freeman, Tom C.
e500260d-7ac7-48df-bf05-00b89a60fdf0
Manson, Jean C.
f1a3d72a-48da-48f1-9ad1-a4312bbf5edf
Alibhai, James
72cc7637-618d-4665-b00e-49ff2db5ca1c
Blanco, Richard A.
5270634c-4307-46f6-a977-32a00cd15743
Barria, Pedro Piccardo
8d461929-4d9a-4e30-b513-2352c0a6225a
Caughey, Byron
e77fea10-2aa4-4d2c-afef-22dbc62f96d9
Perry, Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4
Freeman, Tom C.
e500260d-7ac7-48df-bf05-00b89a60fdf0
Manson, Jean C.
f1a3d72a-48da-48f1-9ad1-a4312bbf5edf

Alibhai, James, Blanco, Richard A., Barria, Pedro Piccardo, Caughey, Byron, Perry, Hugh, Freeman, Tom C. and Manson, Jean C. (2016) Distribution of misfolded prion protein seeding activity alone does not predict regions of neurodegeneration. PLoS Biology. (doi:10.1371/journal.pbio.1002579).

Record type: Article

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 is 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 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 11 novel homeostatic response in all regions and an innate immune response restricted to sites of 12 neurodegeneration. Therefore accumulation of misfolded prion protein alone does not define targeting 13 of neurodegeneration which instead results only when misfolded prion protein accompanies a specific 14 innate immune response.

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Accepted/In Press date: 21 October 2016
e-pub ahead of print date: 23 November 2016
Published date: 23 November 2016
Organisations: Biomedicine

Identifiers

Local EPrints ID: 402435
URI: https://eprints.soton.ac.uk/id/eprint/402435
ISSN: 1544-9173
PURE UUID: 57379a0f-8404-4b32-bb59-f7d97d6977af

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Date deposited: 09 Nov 2016 10:28
Last modified: 09 Jan 2018 17:44

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