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    Dissociation of Prion Protein Amyloid Seeding from Transmission of a Spongiform Encephalopathy

    Date
    2013-11-15
    Author
    Piccardo, Pedro
    King, Declan
    Telling, Glenn
    Manson, Jean C.
    Barron, Rona
    Metadata
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    Citation
    Piccardo, P., King, D., Telling, G., Manson, J.C. and Barron, R.M. (2013) ‘Dissociation of prion protein amyloid seeding from transmission of a spongiform encephalopathy’, Journal of Virology, 87(22), pp. 12349–12356. Available at: https://doi.org/10.1128/JVI.00673-13.
    Abstract
    Misfolding and aggregation of proteins are common pathogenic mechanisms of a group of diseases called proteinopathies. The formation and spread of proteinaceous lesions within and between individuals were first described in prion diseases and proposed as the basis of their infectious nature. Recently, a similar “prion-like” mechanism of transmission has been proposed in other neurodegenerative diseases such as Alzheimer's disease. We investigated if misfolding and aggregation of corrupted prion protein (PrPTSE) are always associated with horizontal transmission of disease. Knock-in transgenic mice (101LL) expressing mutant PrP (PrP-101L) that are susceptible to disease but do not develop any spontaneous neurological phenotype were inoculated with (i) brain extracts containing PrPTSE from healthy 101LL mice with PrP plaques in the corpus callosum or (ii) brain extracts from mice overexpressing PrP-101L with neurological disease, severe spongiform encephalopathy, and formation of proteinase K-resistant PrPTSE. In all instances, 101LL mice developed PrP plaques in the area of inoculation and vicinity in the absence of clinical disease or spongiform degeneration of the brain. Importantly, 101LL mice did not transmit disease on serial passage, ruling out the presence of subclinical infection. Thus, in both experimental models the formation of PrPTSE is not infectious. These results have implications for the interpretation of tests based on the detection of protein aggregates and suggest that de novo formation of PrPTSE in the host does not always result in a transmissible prion disease. In addition, these results question the validity of assuming that all diseases due to protein misfolding can be transmitted between individuals.
    URI
    https://eresearch.qmu.ac.uk/handle/20.500.12289/12707
    Official URL
    https://doi.org/10.1128/JVI.00673-13
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    • Dietetics, Nutrition and Biological Sciences

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