{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T15:07:33Z","timestamp":1789657653483,"version":"4.0.1"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>\n                    \u03b1-Synuclein oligomer (\u03b1SynO)-mediated neurodegeneration is a hallmark of Parkinson\u2019s disease (PD) pathogenesis, yet the molecular mechanisms mediating this toxicity remain elusive. In this study, we investigated the cellular prion protein (PrP\n                    <jats:sup>C<\/jats:sup>\n                    ) as a key modulator of \u03b1SynO-induced neurodegeneration using an integrative translational approach combining human transcriptomic analysis with\n                    <jats:italic>in vivo<\/jats:italic>\n                    bidirectional genetic modulation in mice. Bioinformatics analysis of postmortem substantia nigra samples revealed that the\n                    <jats:italic>PRNP<\/jats:italic>\n                    gene is significantly upregulated in idiopathic PD patients, with its co-expression network enriched for plasma membrane raft organization and synaptic vesicle dynamics. Single-cell RNA-seq confirmed that\n                    <jats:italic>PRNP<\/jats:italic>\n                    expression is predominantly neuronal and expressed at low levels in microglia. To validate these findings, we performed intrastriatal \u03b1SynO injections in PrP\n                    <jats:sup>C<\/jats:sup>\n                    -knockout (PrnpKO), PrP\n                    <jats:sup>C<\/jats:sup>\n                    -overexpressing (Tg20), and wild-type (WT) mice. Immunohistochemical analysis at 30\u202fdays post-injection revealed that dopaminergic vulnerability was determined by PrP\n                    <jats:sup>C<\/jats:sup>\n                    expression levels. Tg20 mice exhibited reduced tyrosine hydroxylase immunoreactivity in the caudate-putamen, while PrnpKO mice were protected. Behavioral assessment showed that PrP\n                    <jats:sup>C<\/jats:sup>\n                    levels modulate baseline motor performance, with Tg20-\u03b1SynO mice consistently displaying the most severe motor impairment. RT-qPCR analysis of striatal transcripts\/mRNA levels revealed genotype-specific neuroinflammatory responses to \u03b1SynO. WT mice mounted a selective anti-inflammatory\n                    <jats:italic>Arginase 1<\/jats:italic>\n                    response, PrnpKO mice partially resolved their basal pro-inflammatory profile, whereas Tg20 mice exhibited pro-inflammatory exacerbation with significant upregulation of\n                    <jats:italic>Tnf\u03b1<\/jats:italic>\n                    and\n                    <jats:italic>Il1\u03b2<\/jats:italic>\n                    . Together, these findings identify PrP\n                    <jats:sup>C<\/jats:sup>\n                    expression levels as an important modulator of nigrostriatal vulnerability and neuroinflammatory phenotype in response to \u03b1SynO, supporting the hypothesis that PrP\n                    <jats:sup>C<\/jats:sup>\n                    contributes to \u03b1SynO-mediated pathogenic mechanisms.\n                  <\/jats:p>","DOI":"10.3389\/fnins.2026.1913279","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T14:37:03Z","timestamp":1789655823000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cellular prion protein levels modulate nigrostriatal vulnerability to \u03b1-synuclein oligomers in Parkinson\u2019s disease"],"prefix":"10.3389","volume":"20","author":[{"given":"Flavio","family":"de Souza J\u00fanyor","sequence":"first","affiliation":[{"name":"Laboratory of Glial Cell Biology, Biomedical Sciences Institute, Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe Saceanu","family":"Leser","sequence":"additional","affiliation":[{"name":"Laboratory of Glial Cell Biology, Biomedical Sciences Institute, Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]},{"name":"Department of Internal Medicine, Cardiovascular Research Center, Yale University School of Medicine","place":["New Haven, CT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"de Souza Albuquerque","sequence":"additional","affiliation":[{"name":"Laboratory of Glial Cell Biology, Biomedical Sciences Institute, Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"de Barros-Telles","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pharmacology, Biomedical Sciences Institute, Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luana","family":"Heimfarth","sequence":"additional","affiliation":[{"name":"Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]},{"name":"Institute of Medical Biochemistry Leopoldo de Meis, Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"da Silva Andrade","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pharmacology, Biomedical Sciences Institute, Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla Moreira","family":"Furtado","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology Applied to Biomedicine, Biomedical Sciences Institute, Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena Fortuna","family":"da Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology Applied to Biomedicine, Biomedical Sciences Institute, Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe Cau\u00e3 Pinheiro","family":"dos Santos","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology Applied to Biomedicine, Biomedical Sciences Institute, Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Leandra Sant'Anna Ramos","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pharmacology, Biomedical Sciences Institute, Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio T.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]},{"name":"Institute of Medical Biochemistry Leopoldo de Meis, Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Braga","sequence":"additional","affiliation":[{"name":"N\u00facleo Multidisciplinar de Pesquisas em Biologia, NUMPEX-Bio, Universidade Federal do Rio de Janeiro","place":["Duque de Caxias, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celina Garcia","family":"da Fonseca","sequence":"additional","affiliation":[{"name":"Laboratory of Glial Cell Biology, Biomedical Sciences Institute, Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]},{"name":"Biomedical Sciences Institute, Universidade Federal do Rio de Janeiro","place":["Maca\u00e9, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilda Angela","family":"Neves","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pharmacology, Biomedical Sciences Institute, Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"Rom\u00e3o","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology Applied to Biomedicine, Biomedical Sciences Institute, Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia Regina Souza","family":"Lima","sequence":"additional","affiliation":[{"name":"Laboratory of Glial Cell Biology, Biomedical Sciences Institute, Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1001\/jama.2019.22360","article-title":"Diagnosis and treatment of Parkinson disease: a review","volume":"323","author":"Armstrong","year":"2020","journal-title":"JAMA"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"10050","DOI":"10.1038\/s41598-017-10236-x","article-title":"\u0391-Synuclein amyloids hijack prion protein to gain cell entry, facilitate cell-to-cell spreading and block prion replication","volume":"7","author":"Auli\u0107","year":"2017","journal-title":"Sci. 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