Treatment of prion disease with heterologous prion proteins

Pamela J. Skinner, Hyeon O. Kim, Damani Bryant, Nikilyn J. Kinzel, Cavan Reilly, Suzette A. Priola, Anne E. Ward, Patricia A. Goodman, Katherine Olson, Davis M. Seelig

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Prion diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep are fatal neurodegenerative diseases for which there is no effective treatment. The pathology of these diseases involves the conversion of a protease sensitive form of the cellular prion protein (PrPC) into a protease resistant infectious form (PrPsc or PrPres). Both in vitro (cell culture and cell free conversion assays) and in vivo (animal) studies have demonstrated the strong dependence of this conversion process on protein sequence homology between the initial prion inoculum and the host's own cellular prion protein. The presence of non-homologous (heterologous) proteins is often inhibitory to this conversion process. We hypothesize that the presence of heterologous prion proteins from one species might therefore constitute an effective treatment for prion disease in another species. To test this hypothesis, we infected mice intracerebrally with murine adapted RML-Chandler scrapie and treated them with heterologous prion protein (purified bacterially expressed recombinant hamster prion protein) or vehicle alone. Treated animals demonstrated reduced disease associated pathology, decreased accumulation of protease-resistant disease-associated prion protein, with delayed onset of clinical symptoms and motor deficits. This was concomitant with significantly increased survival times relative to mock-treated animals. These results provide proof of principle that recombinant hamster prion proteins can effectively and safely inhibit prion disease in mice, and suggest that hamster or other non-human prion proteins may be a viable treatment for prion diseases in humans.

Original languageEnglish (US)
Article numbere0131993
JournalPloS one
Volume10
Issue number7
DOIs
StatePublished - Jul 2 2015

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Prion Diseases
prion diseases
Prions
prions
Cricetinae
Scrapie
Peptide Hydrolases
hamsters
Animals
Pathology
proteinases
scrapie
PrPC Proteins
Bovine Spongiform Encephalopathy
mice
Amino Acid Sequence Homology
Creutzfeldt-Jakob Syndrome
Neurodegenerative diseases
Prion Proteins
animals

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Treatment of prion disease with heterologous prion proteins. / Skinner, Pamela J.; Kim, Hyeon O.; Bryant, Damani; Kinzel, Nikilyn J.; Reilly, Cavan; Priola, Suzette A.; Ward, Anne E.; Goodman, Patricia A.; Olson, Katherine; Seelig, Davis M.

In: PloS one, Vol. 10, No. 7, e0131993, 02.07.2015.

Research output: Contribution to journalArticle

Skinner, PJ, Kim, HO, Bryant, D, Kinzel, NJ, Reilly, C, Priola, SA, Ward, AE, Goodman, PA, Olson, K & Seelig, DM 2015, 'Treatment of prion disease with heterologous prion proteins', PloS one, vol. 10, no. 7, e0131993. https://doi.org/10.1371/journal.pone.0131993
Skinner, Pamela J. ; Kim, Hyeon O. ; Bryant, Damani ; Kinzel, Nikilyn J. ; Reilly, Cavan ; Priola, Suzette A. ; Ward, Anne E. ; Goodman, Patricia A. ; Olson, Katherine ; Seelig, Davis M. / Treatment of prion disease with heterologous prion proteins. In: PloS one. 2015 ; Vol. 10, No. 7.
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