Open AccessThe cellular prion protein interacts with and promotes the activity of Na,K-ATPases
Author(s) -
Declan Williams,
Mohadeseh Mehrabian,
Hamza Arshad,
Shehab Eid,
Christopher Sackmann,
Wenda Zhao,
Xinzhu Wang,
Farinaz Ghodrati,
Claire Verkuyl,
Joel C. Watts,
Gerold SchmittUlms
Publication year - 2021
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0258682
Subject(s) - microbiology and biotechnology , glial fibrillary acidic protein , biology , cell culture , atpase , chemistry , biochemistry , enzyme , immunohistochemistry , genetics , immunology
The prion protein (PrP) is best known for its ability to cause fatal neurodegenerative diseases in humans and animals. Here, we revisited its molecular environment in the brain using a well-developed affinity-capture mass spectrometry workflow that offers robust relative quantitation. The analysis confirmed many previously reported interactions. It also pointed toward a profound enrichment of Na,K-ATPases (NKAs) in proximity to cellular PrP (PrP C ). Follow-on work validated the interaction, demonstrated partial co-localization of the ATP1A1 and PrP C , and revealed that cells exposed to cardiac glycoside (CG) inhibitors of NKAs exhibit correlated changes to the steady-state levels of both proteins. Moreover, the presence of PrP C was observed to promote the ion uptake activity of NKAs in a human co-culture paradigm of differentiated neurons and glia cells, and in mouse neuroblastoma cells. Consistent with this finding, changes in the expression of 5’-nucleotidase that manifest in wild-type cells in response to CG exposure can also be observed in untreated PrP C -deficient cells. Finally, the endoproteolytic cleavage of the glial fibrillary acidic protein, a hallmark of late-stage prion disease, can also be induced by CGs, raising the prospect that a loss of NKA activity may contribute to the pathobiology of prion diseases.