Cardiac glycoside-mediated turnover of Na, K-ATPases as a rational approach to reducing cell surface levels of the cellular prion protein

• Published in: PloS one Vol. 17; no. 7; p. e0270915
• Main Authors: Mehrabian, Mohadeseh, Wang, Xinzhu, Eid, Shehab, Yan, Bei Qi, Grinberg, Mark, Siegner, Murdock, Sackmann, Christopher, Sulman, Muhammad, Zhao, Wenda, Williams, Declan, Schmitt-Ulms, Gerold
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 01.07.2022; Public Library of Science (PLoS)
• Subjects: Adenosine triphosphatase; Astrocytes; Biology and Life Sciences; Brain; Cardiac glycosides; Cathepsin B; Cell surface; Cellular proteins; Cysteine proteinase; Disease; Evaluation; Glycosides; Medicine and Health Sciences; Metabolism; Neurodegenerative diseases; Physical Sciences; Physiological aspects; Prion protein; Prions; Properties; Proteins; Research and Analysis Methods
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0270915

It is widely anticipated that a reduction of brain levels of the cellular prion protein (PrP C ) can prolong survival in a group of neurodegenerative diseases known as prion diseases. To date, efforts to decrease steady-state PrP C 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 C in the brain, unlocking an opportunity for an indirect PrP C 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 C levels. The mechanism of action underpinning this outcome relies primarily on a subset of CGs engaging the ATP1A1 isoform, one of three α subunits of Na,K-ATPases expressed in brain cells. Upon CG docking to ATP1A1, the ligand receptor complex, and PrP C along with it, is internalized by the cell. Subsequently, PrP C 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.