{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T09:34:13Z","timestamp":1771061653087,"version":"3.50.1"},"reference-count":85,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T00:00:00Z","timestamp":1656633600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004089","name":"Krembil Foundation","doi-asserted-by":"publisher","award":["507571"],"award-info":[{"award-number":["507571"]}],"id":[{"id":"10.13039\/501100004089","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Arnold Irwin family"},{"name":"Borden Rosiak family"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>It is widely anticipated that a reduction of brain levels of the cellular prion protein (PrP<jats:sup>C<\/jats:sup>) can prolong survival in a group of neurodegenerative diseases known as prion diseases. To date, efforts to decrease steady-state PrP<jats:sup>C<\/jats:sup> levels by targeting this protein directly with small molecule drug-like compounds have largely been unsuccessful. Recently, we reported Na,K-ATPases to reside in immediate proximity to PrP<jats:sup>C<\/jats:sup> in the brain, unlocking an opportunity for an indirect PrP<jats:sup>C<\/jats:sup> targeting approach that capitalizes on the availability of potent cardiac glycosides (CGs). Here, we report that exposure of human co-cultures of neurons and astrocytes to non-toxic nanomolar levels of CGs causes profound reductions in PrP<jats:sup>C<\/jats:sup> levels. The mechanism of action underpinning this outcome relies primarily on a subset of CGs engaging the ATP1A1 isoform, one of three \u03b1 subunits of Na,K-ATPases expressed in brain cells. Upon CG docking to ATP1A1, the ligand receptor complex, and PrP<jats:sup>C<\/jats:sup> along with it, is internalized by the cell. Subsequently, PrP<jats:sup>C<\/jats:sup> is channeled to the lysosomal compartment where it is digested in a manner that can be rescued by silencing the cysteine protease cathepsin B. These data signify that the repurposing of CGs may be beneficial for the treatment of prion disorders.<\/jats:p>","DOI":"10.1371\/journal.pone.0270915","type":"journal-article","created":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T17:37:24Z","timestamp":1656697044000},"page":"e0270915","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["Cardiac glycoside-mediated turnover of Na, K-ATPases as a rational approach to reducing cell surface levels of the cellular prion protein"],"prefix":"10.1371","volume":"17","author":[{"given":"Mohadeseh","family":"Mehrabian","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinzhu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shehab","family":"Eid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bei 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