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Cardiac glycoside-mediated turnover of Na, K-ATPases as a rational approach to reducing cell surface levels of the cellular prion protein.
Mehrabian, Mohadeseh; Wang, Xinzhu; Eid, Shehab; Yan, Bei Qi; Grinberg, Mark; Siegner, Murdock; Sackmann, Christopher; Sulman, Muhammad; Zhao, Wenda; Williams, Declan; Schmitt-Ulms, Gerold.
Afiliación
  • Mehrabian M; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, Toronto, Ontario, Canada.
  • Wang X; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
  • Eid S; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, Toronto, Ontario, Canada.
  • Yan BQ; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
  • Grinberg M; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, Toronto, Ontario, Canada.
  • Siegner M; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
  • Sackmann C; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, Toronto, Ontario, Canada.
  • Sulman M; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
  • Zhao W; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, Toronto, Ontario, Canada.
  • Williams D; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, Toronto, Ontario, Canada.
  • Schmitt-Ulms G; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
PLoS One ; 17(7): e0270915, 2022.
Article en En | MEDLINE | ID: mdl-35776750
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Priones / Glicósidos Cardíacos / Enfermedades por Prión Límite: Humans Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2022 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Priones / Glicósidos Cardíacos / Enfermedades por Prión Límite: Humans Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2022 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos