{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:46:02Z","timestamp":1791351962533,"version":"4.3.1"},"reference-count":46,"publisher":"National Academy of Sciences","issue":"20","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2002,10]]},"abstract":"<jats:p>\n                    Our discovery of dominant-negative inhibition of prion formation in cultured cells provided an explanation for the resistance of some sheep to scrapie and humans to Creutzfeldt\u2013Jakob disease. To determine whether dominant-negative inhibition occurs\n                    <jats:italic>in vivo<\/jats:italic>\n                    , we produced transgenic (Tg) mice expressing prion protein (PrP) with either the Q167R or Q218K mutation alone or in combination with wild-type (wt) PrP. Tg(MoPrP,Q167R)\n                    <jats:italic>Prnp<\/jats:italic>\n                    <jats:sup>0\/0<\/jats:sup>\n                    mice expressing mutant PrP at levels equal to non-Tg mice remained healthy for &gt;550 days, indicating that inoculation with prions did not cause disease. Immunoblots of brain homogenates and histologic analysis did not reveal abnormalities. Tg(MoPrP,Q167R)\n                    <jats:italic>Prnp<\/jats:italic>\n                    <jats:sup>+\/+<\/jats:sup>\n                    mice expressing both mutant and wt PrP did not exhibit neurologic dysfunction, but their brains revealed low levels of the PrP pathogenic isoform (PrP\n                    <jats:sup>Sc<\/jats:sup>\n                    ), and sections showed numerous vacuoles and severe astrocytic gliosis at 300 days after inoculation. Both Tg(MoPrP,Q218K)\n                    <jats:italic>Prnp<\/jats:italic>\n                    <jats:sup>0\/0<\/jats:sup>\n                    and Tg(MoPrP,Q218K)\n                    <jats:italic>Prnp<\/jats:italic>\n                    <jats:sup>+\/+<\/jats:sup>\n                    mice expressing high levels of the transgene product remained healthy for &gt;300 days after inoculation. Neither PrP\n                    <jats:sup>Sc<\/jats:sup>\n                    nor neuropathologic changes were found. Our studies demonstrate that although dominant-negative inhibition of wt PrP\n                    <jats:sup>Sc<\/jats:sup>\n                    formation occurs, expression of the dominant-negative PrP at the same level as wt PrP does not prevent prion formation completely. However, expression of dominant-negative PrP alone had no deleterious effects on the mice and did not support prion propagation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.182425299","type":"journal-article","created":{"date-parts":[[2002,10,1]],"date-time":"2002-10-01T12:58:07Z","timestamp":1033477087000},"page":"13079-13084","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":144,"title":["Dominant-negative inhibition of prion replication in transgenic mice"],"prefix":"10.1073","volume":"99","author":[{"given":"V\u00e9ronique","family":"Perrier","sequence":"first","affiliation":[{"name":"Institute for Neurodegenerative Diseases and Departments of Pathology, Biochemistry and Biophysics, Cellular and Molecular Pharmacology, Medicine, and Neurology, University of California, San Francisco, CA 94143-0518"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyotoshi","family":"Kaneko","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases and Departments of Pathology, Biochemistry and Biophysics, Cellular and Molecular Pharmacology, Medicine, and Neurology, University of California, San Francisco, CA 94143-0518"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiri","family":"Safar","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases and Departments of Pathology, Biochemistry and Biophysics, Cellular and Molecular Pharmacology, Medicine, and Neurology, University of California, San Francisco, CA 94143-0518"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Vergara","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases and Departments of Pathology, Biochemistry and Biophysics, Cellular and Molecular Pharmacology, Medicine, and Neurology, University of California, San Francisco, CA 94143-0518"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Tremblay","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases and Departments of Pathology, Biochemistry and Biophysics, Cellular and Molecular Pharmacology, Medicine, and Neurology, University of California, San Francisco, CA 94143-0518"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"DeArmond","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases and Departments of Pathology, Biochemistry and Biophysics, Cellular and Molecular Pharmacology, Medicine, and Neurology, University of California, San Francisco, CA 94143-0518"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fred E.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases and Departments of Pathology, Biochemistry and Biophysics, Cellular and Molecular Pharmacology, Medicine, and Neurology, University of California, San Francisco, CA 94143-0518"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley B.","family":"Prusiner","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases and Departments of Pathology, Biochemistry and Biophysics, Cellular and Molecular Pharmacology, Medicine, and Neurology, University of California, San Francisco, CA 94143-0518"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew C.","family":"Wallace","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases and Departments of Pathology, Biochemistry and Biophysics, Cellular and Molecular Pharmacology, Medicine, and Neurology, University of California, San Francisco, CA 94143-0518"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2002,9,23]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.37.8.1271"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.161274798"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.74.10.4894-4897.2000"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.25.14529"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.21.12117"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1998.71062534.x"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.11.6073"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(99)11419-3"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/35089090"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.151242598"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.287.5457.1503"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/22124"},{"key":"e_1_3_3_13_2","doi-asserted-by":"crossref","unstructured":"Bard F. 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