Treatment of Prion Disease with Heterologous Prion Proteins
Publication Date
July 02, 2015
Journal
PLOS ONE
Authors
Pamela J. Skinner, Hyeon O. Kim, Damani Bryant, Nikilyn J. Kinzel, et al
Volume
10
Issue
7
Pages
e0131993
DOI
https://dx.plos.org/10.1371/journal.pone.0131993
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0131993
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/26134409
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489745
Europe PMC
http://europepmc.org/abstract/MED/26134409
Web of Science
000358154400091
Scopus
84940055371
Mendeley
http://www.mendeley.com/research/treatment-prion-disease-heterologous-prion-proteins
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Mendeley | Further Information

{"title"=>"Treatment of prion disease with heterologous prion proteins", "type"=>"journal", "authors"=>[{"first_name"=>"Pamela J.", "last_name"=>"Skinner", "scopus_author_id"=>"35508781000"}, {"first_name"=>"Hyeon O.", "last_name"=>"Kim", "scopus_author_id"=>"56007013500"}, {"first_name"=>"Damani", "last_name"=>"Bryant", "scopus_author_id"=>"8227373000"}, {"first_name"=>"Nikilyn J.", "last_name"=>"Kinzel", "scopus_author_id"=>"6508195096"}, {"first_name"=>"Cavan", "last_name"=>"Reilly", "scopus_author_id"=>"7103120251"}, {"first_name"=>"Suzette A.", "last_name"=>"Priola", "scopus_author_id"=>"7003711000"}, {"first_name"=>"Anne E.", "last_name"=>"Ward", "scopus_author_id"=>"16445229000"}, {"first_name"=>"Patricia A.", "last_name"=>"Goodman", "scopus_author_id"=>"56800044800"}, {"first_name"=>"Katherine", "last_name"=>"Olson", "scopus_author_id"=>"16237009200"}, {"first_name"=>"Davis M.", "last_name"=>"Seelig", "scopus_author_id"=>"14833418400"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"26134409", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0131993", "pui"=>"605761525", "isbn"=>"1932-6203 (Electronic)\r1932-6203 (Linking)", "scopus"=>"2-s2.0-84940055371", "sgr"=>"84940055371"}, "id"=>"1b84b187-be1c-3edf-a76b-da837a29b089", "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.", "link"=>"http://www.mendeley.com/research/treatment-prion-disease-heterologous-prion-proteins", "reader_count"=>27, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>5, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Other"=>3, "Student > Bachelor"=>7, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>5, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Other"=>3, "Student > Bachelor"=>7, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>7, "Agricultural and Biological Sciences"=>9, "Medicine and Dentistry"=>4, "Veterinary Science and Veterinary Medicine"=>3, "Computer Science"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>9}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>7}, "Unspecified"=>{"Unspecified"=>2}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>3}}, "reader_count_by_country"=>{"France"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2160330"], "description"=>"<p>Western blot analysis of prion protein from the brain (A) and spleen (B) from scrapie-infected mice that were mock-treated with vehicle alone, treated with a relatively low dose of hamster prion protein, or treated with a relatively high dose of hamster prion protein, collected at 108 days post-scrapie infection. Mouse antibodies directed against PrP (SAF83) were used to detect PrP<sup>C</sup> and Proteinase K treated (PK) PrP<sup>res</sup>. GAPDH staining was used as a loading control. The average density of PrP<sup>res</sup> bands for each group is shown for the brain (C) and spleen (D). Significantly lower levels of PrP<sup>res</sup> were observed in the high-dose treated animals relative to mock-treated animals (<i>p</i> = 0.0286 by the Wilcoxon rank sum test, also, see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0131993#pone.0131993.g003\" target=\"_blank\">Fig 3</a>). There was no observed difference between the low dose and mock infected groups (<i>p</i> = 0.686 by the Wilcoxon rank sum test).</p>", "links"=>[], "tags"=>["heterologous prion proteins", "heterologous prion protein", "hamster prion proteins", "conversion process", "protein sequence homology", "Prion Disease", "hamster prion protein", "Heterologous Prion Proteins Prion diseases", "prion protein"], "article_id"=>1472021, "categories"=>["Biological Sciences"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0131993.g001", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Reduced_PrP_res_accumulation_in_brain_and_spleen_of_high_dose_treated_mice_/1472021", "title"=>"Reduced PrP<sup>res</sup> accumulation in brain and spleen of high-dose-treated mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-02 03:11:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2160337"], "description"=>"<p>The hanging wire assay was used as an objective measure of motor coordination and muscle strength. The graphs show the results of A) mock-treated mice, B) uninfected age matched mice, C) low-dose-treated mice, and D) high-dose-treated mice. E) Shows the mean values for each group. The X-axis shows the day post-infection and the Y-axis shows the time of latency to fall from a wire grid in a 120 second trial. In A-D), individual averages of triplicate trials are shown with error bars showing the standard deviation. Mixed model analysis (which uses the data from all time points to test for differences between groups) finds significant differences between both treatment dose groups and the mock infected group (<i>p</i><0.001 for both tests). Significant differences (p<0.001) were also seen between the three groups (mock, low dose, high dose) and the uninfected age matched mice. Note, one of the low-dose treated animals included in this study (indicated with an asterisk in C) was euthanized due to the development of a skin disease towards the end of the study at 347 dpi.</p>", "links"=>[], "tags"=>["heterologous prion proteins", "heterologous prion protein", "hamster prion proteins", "conversion process", "protein sequence homology", "Prion Disease", "hamster prion protein", "Heterologous Prion Proteins Prion diseases", "prion protein"], "article_id"=>1472027, "categories"=>["Biological Sciences"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0131993.g003", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Treatment_with_heterologous_recombinant_HaPrP_delayed_loss_of_motor_function_/1472027", "title"=>"Treatment with heterologous recombinant HaPrP delayed loss of motor function.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-02 03:11:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2160338"], "description"=>"<p>Kaplan-Meier plots showing the time at which mock-treated (orange, n = 5), low-dose-treated (blue, n = 5), high-dose-treated mice (purple, n = 6) and uninfected (red, n = 10) developed A) detectable symptoms associated with scrapie infection, including ataxic gait, weight loss, and kyphosis, and B) time of survival. We tested for differences between groups using a modified version of the Gehan-Wilcoxon test and found a statistically significant difference between the mock infected group and the high dose group (<i>p</i> = 0.0348). The low-dose group was not significantly different than the mock-treated control group. The uninfected control mice showed significantly longer survival times than the three groups of infected mice; uninfected versus mock (p = 0.008), uninfected versus low dose (p = 0.006) and uninfected versus high dose (p = 0.0201).</p>", "links"=>[], "tags"=>["heterologous prion proteins", "heterologous prion protein", "hamster prion proteins", "conversion process", "protein sequence homology", "Prion Disease", "hamster prion protein", "Heterologous Prion Proteins Prion diseases", "prion protein"], "article_id"=>1472028, "categories"=>["Biological Sciences"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0131993.g004", "stats"=>{"downloads"=>3, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Treatment_with_heterologous_recombinant_HaPrP_delayed_the_onset_of_symptoms_and_prolonged_survival_/1472028", "title"=>"Treatment with heterologous recombinant HaPrP delayed the onset of symptoms and prolonged survival.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-02 03:11:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2160334"], "description"=>"<p>Anti-GFAP antibody (brown) and hematoxylin (blue) staining in A) whole brain and B) enlargement showing thalamus. For comparison, similar staining is presented from an aged matched negative control animal that was mock-infected with a 1% homogenate of normal mouse brain. For this analysis, regions of brain not present in all sections were removed (including cerebellum, brainstem, and olfactory bulb). Scale bars = 200 μm. Levels of GFAP staining are shown for C) whole brain, D) hippocamus, and E) thalamus. The high-dose-treated mice showed a trend of less GFAP accumulation in the brain compared to mock-treated mice (<i>p</i> = 0.103 by a 2 sample <i>t</i>-test on the logarithms of the levels), whereas no difference was detected between the low-dose-treated and mock infected mice (<i>p</i> = 0.906 again by a 2 sample <i>t</i>-test). Decreases in high-dose treated verses mock-treated mice were most pronounced in the thalamus (<i>p</i> = 0.000557 by a 2 sample <i>t</i>-test); no significant differences in staining were seen amongst groups in the hippocampus (<i>p</i> = 0.825 for the high-dose group compared to the mock treated group and <i>p</i> = 0.839 for the low-dose group compared to the mock treated group, again with a 2 sample <i>t</i>-test).</p>", "links"=>[], "tags"=>["heterologous prion proteins", "heterologous prion protein", "hamster prion proteins", "conversion process", "protein sequence homology", "Prion Disease", "hamster prion protein", "Heterologous Prion Proteins Prion diseases", "prion protein"], "article_id"=>1472025, "categories"=>["Biological Sciences"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0131993.g002", "stats"=>{"downloads"=>3, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Decreased_astrocytosis_in_brains_of_high_dose_treated_mice_/1472025", "title"=>"Decreased astrocytosis in brains of high-dose treated mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-02 03:11:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/2160348", "https://ndownloader.figshare.com/files/2160349", "https://ndownloader.figshare.com/files/2160350"], "description"=>"<div><p>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 (PrP<sup>C</sup>) into a protease resistant infectious form (PrP<sup>sc</sup> or PrP<sup>res</sup>). Both <i>in vitro</i> (cell culture and cell free conversion assays) and <i>in vivo</i> (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.</p></div>", "links"=>[], "tags"=>["heterologous prion proteins", "heterologous prion protein", "hamster prion proteins", "conversion process", "protein sequence homology", "Prion Disease", "hamster prion protein", "Heterologous Prion Proteins Prion diseases", "prion protein"], "article_id"=>1472037, "categories"=>["Biological Sciences"], "users"=>["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"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0131993.s001", "https://dx.doi.org/10.1371/journal.pone.0131993.s002", "https://dx.doi.org/10.1371/journal.pone.0131993.s003"], "stats"=>{"downloads"=>9, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Treatment_of_Prion_Disease_with_Heterologous_Prion_Proteins_/1472037", "title"=>"Treatment of Prion Disease with Heterologous Prion Proteins", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-07-02 03:11:38"}

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{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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