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

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-l...

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Published inPloS 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
LanguageEnglish
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
Online AccessGet full text
ISSN1932-6203
1932-6203
DOI10.1371/journal.pone.0270915

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Abstract 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.
AbstractList 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.
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.
It is widely anticipated that a reduction of brain levels of the cellular prion protein (PrPC) can prolong survival in a group of neurodegenerative diseases known as prion diseases. To date, efforts to decrease steady-state PrPC 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 PrPC in the brain, unlocking an opportunity for an indirect PrPC 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 PrPC 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 PrPC along with it, is internalized by the cell. Subsequently, PrPC 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.
It is widely anticipated that a reduction of brain levels of the cellular prion protein (PrPC) can prolong survival in a group of neurodegenerative diseases known as prion diseases. To date, efforts to decrease steady-state PrPC 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 PrPC in the brain, unlocking an opportunity for an indirect PrPC 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 PrPC 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 PrPC along with it, is internalized by the cell. Subsequently, PrPC 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.It is widely anticipated that a reduction of brain levels of the cellular prion protein (PrPC) can prolong survival in a group of neurodegenerative diseases known as prion diseases. To date, efforts to decrease steady-state PrPC 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 PrPC in the brain, unlocking an opportunity for an indirect PrPC 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 PrPC 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 PrPC along with it, is internalized by the cell. Subsequently, PrPC 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.
It is widely anticipated that a reduction of brain levels of the cellular prion protein (PrP.sup.C) can prolong survival in a group of neurodegenerative diseases known as prion diseases. To date, efforts to decrease steady-state PrP.sup.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.sup.C in the brain, unlocking an opportunity for an indirect PrP.sup.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.sup.C levels. The mechanism of action underpinning this outcome relies primarily on a subset of CGs engaging the ATP1A1 isoform, one of three [alpha] subunits of Na,K-ATPases expressed in brain cells. Upon CG docking to ATP1A1, the ligand receptor complex, and PrP.sup.C along with it, is internalized by the cell. Subsequently, PrP.sup.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.
Audience Academic
Author Schmitt-Ulms, Gerold
Yan, Bei Qi
Grinberg, Mark
Eid, Shehab
Zhao, Wenda
Williams, Declan
Mehrabian, Mohadeseh
Sackmann, Christopher
Siegner, Murdock
Sulman, Muhammad
Wang, Xinzhu
AuthorAffiliation 1 Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, Toronto, Ontario, Canada
2 Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada
Ruhr University Bochum, GERMANY
AuthorAffiliation_xml – name: 1 Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, Toronto, Ontario, Canada
– name: 2 Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada
– name: Ruhr University Bochum, GERMANY
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  orcidid: 0000-0001-6962-0919
  surname: Schmitt-Ulms
  fullname: Schmitt-Ulms, Gerold
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Current address: CCRM, Toronto, Ontario, Canada
Current address: Sarepta Therapeutics, Cambridge, Massachusetts, United States of America
Competing Interests: GS, MM and DW declare that they are co-inventors on a provisional patent (United States Provisional Application No. 63/159,289) named ‘Compounds and methods to treat prion and related diseases’ describing the use of cardiac glycosides for the purpose of reducing steady-state levels of PrPC. No other competing interests exist, and this provisional patent does not alter the adherence of these authors to all PLOS ONE policies on sharing data and materials.
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Snippet 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...
It is widely anticipated that a reduction of brain levels of the cellular prion protein (PrP.sup.C) can prolong survival in a group of neurodegenerative...
It is widely anticipated that a reduction of brain levels of the cellular prion protein (PrPC) can prolong survival in a group of neurodegenerative diseases...
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...
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SubjectTerms 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
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Title Cardiac glycoside-mediated turnover of Na, K-ATPases as a rational approach to reducing cell surface levels of the cellular prion protein
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http://dx.doi.org/10.1371/journal.pone.0270915
Volume 17
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