Cargando…

The prion protein constitutively controls neuronal store-operated Ca(2+) entry through Fyn kinase

The prion protein (PrP(C)) is a cell surface glycoprotein mainly expressed in neurons, whose misfolded isoforms generate the prion responsible for incurable neurodegenerative disorders. Whereas PrP(C) involvement in prion propagation is well established, PrP(C) physiological function is still enigma...

Descripción completa

Detalles Bibliográficos
Autores principales: De Mario, Agnese, Castellani, Angela, Peggion, Caterina, Massimino, Maria Lina, Lim, Dmitry, Hill, Andrew F., Sorgato, M. Catia, Bertoli, Alessandro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4623396/
https://www.ncbi.nlm.nih.gov/pubmed/26578881
http://dx.doi.org/10.3389/fncel.2015.00416
_version_ 1782397679373910016
author De Mario, Agnese
Castellani, Angela
Peggion, Caterina
Massimino, Maria Lina
Lim, Dmitry
Hill, Andrew F.
Sorgato, M. Catia
Bertoli, Alessandro
author_facet De Mario, Agnese
Castellani, Angela
Peggion, Caterina
Massimino, Maria Lina
Lim, Dmitry
Hill, Andrew F.
Sorgato, M. Catia
Bertoli, Alessandro
author_sort De Mario, Agnese
collection PubMed
description The prion protein (PrP(C)) is a cell surface glycoprotein mainly expressed in neurons, whose misfolded isoforms generate the prion responsible for incurable neurodegenerative disorders. Whereas PrP(C) involvement in prion propagation is well established, PrP(C) physiological function is still enigmatic despite suggestions that it could act in cell signal transduction by modulating phosphorylation cascades and Ca(2+) homeostasis. Because PrP(C) binds neurotoxic protein aggregates with high-affinity, it has also been proposed that PrP(C) acts as receptor for amyloid-β (Aβ) oligomers associated with Alzheimer’s disease (AD), and that PrP(C)-Aβ binding mediates AD-related synaptic dysfunctions following activation of the tyrosine kinase Fyn. Here, use of gene-encoded Ca(2+) probes targeting different cell domains in primary cerebellar granule neurons (CGN) expressing, or not, PrP(C), allowed us to investigate whether PrP(C) regulates store-operated Ca(2+) entry (SOCE) and the implication of Fyn in this control. Our findings show that PrP(C) attenuates SOCE, and Ca(2+) accumulation in the cytosol and mitochondria, by constitutively restraining Fyn activation and tyrosine phosphorylation of STIM1, a key molecular component of SOCE. This data establishes the existence of a PrP(C)-Fyn-SOCE triad in neurons. We also demonstrate that treating cerebellar granule and cortical neurons with soluble Aβ((1–42)) oligomers abrogates the control of PrP(C) over Fyn and SOCE, suggesting a PrP(C)-dependent mechanizm for Aβ-induced neuronal Ca(2+) dyshomeostasis.
format Online
Article
Text
id pubmed-4623396
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-46233962015-11-17 The prion protein constitutively controls neuronal store-operated Ca(2+) entry through Fyn kinase De Mario, Agnese Castellani, Angela Peggion, Caterina Massimino, Maria Lina Lim, Dmitry Hill, Andrew F. Sorgato, M. Catia Bertoli, Alessandro Front Cell Neurosci Neuroscience The prion protein (PrP(C)) is a cell surface glycoprotein mainly expressed in neurons, whose misfolded isoforms generate the prion responsible for incurable neurodegenerative disorders. Whereas PrP(C) involvement in prion propagation is well established, PrP(C) physiological function is still enigmatic despite suggestions that it could act in cell signal transduction by modulating phosphorylation cascades and Ca(2+) homeostasis. Because PrP(C) binds neurotoxic protein aggregates with high-affinity, it has also been proposed that PrP(C) acts as receptor for amyloid-β (Aβ) oligomers associated with Alzheimer’s disease (AD), and that PrP(C)-Aβ binding mediates AD-related synaptic dysfunctions following activation of the tyrosine kinase Fyn. Here, use of gene-encoded Ca(2+) probes targeting different cell domains in primary cerebellar granule neurons (CGN) expressing, or not, PrP(C), allowed us to investigate whether PrP(C) regulates store-operated Ca(2+) entry (SOCE) and the implication of Fyn in this control. Our findings show that PrP(C) attenuates SOCE, and Ca(2+) accumulation in the cytosol and mitochondria, by constitutively restraining Fyn activation and tyrosine phosphorylation of STIM1, a key molecular component of SOCE. This data establishes the existence of a PrP(C)-Fyn-SOCE triad in neurons. We also demonstrate that treating cerebellar granule and cortical neurons with soluble Aβ((1–42)) oligomers abrogates the control of PrP(C) over Fyn and SOCE, suggesting a PrP(C)-dependent mechanizm for Aβ-induced neuronal Ca(2+) dyshomeostasis. Frontiers Media S.A. 2015-10-28 /pmc/articles/PMC4623396/ /pubmed/26578881 http://dx.doi.org/10.3389/fncel.2015.00416 Text en Copyright © 2015 De Mario, Castellani, Peggion, Massimino, Lim, Hill, Sorgato and Bertoli. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
De Mario, Agnese
Castellani, Angela
Peggion, Caterina
Massimino, Maria Lina
Lim, Dmitry
Hill, Andrew F.
Sorgato, M. Catia
Bertoli, Alessandro
The prion protein constitutively controls neuronal store-operated Ca(2+) entry through Fyn kinase
title The prion protein constitutively controls neuronal store-operated Ca(2+) entry through Fyn kinase
title_full The prion protein constitutively controls neuronal store-operated Ca(2+) entry through Fyn kinase
title_fullStr The prion protein constitutively controls neuronal store-operated Ca(2+) entry through Fyn kinase
title_full_unstemmed The prion protein constitutively controls neuronal store-operated Ca(2+) entry through Fyn kinase
title_short The prion protein constitutively controls neuronal store-operated Ca(2+) entry through Fyn kinase
title_sort prion protein constitutively controls neuronal store-operated ca(2+) entry through fyn kinase
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4623396/
https://www.ncbi.nlm.nih.gov/pubmed/26578881
http://dx.doi.org/10.3389/fncel.2015.00416
work_keys_str_mv AT demarioagnese theprionproteinconstitutivelycontrolsneuronalstoreoperatedca2entrythroughfynkinase
AT castellaniangela theprionproteinconstitutivelycontrolsneuronalstoreoperatedca2entrythroughfynkinase
AT peggioncaterina theprionproteinconstitutivelycontrolsneuronalstoreoperatedca2entrythroughfynkinase
AT massiminomarialina theprionproteinconstitutivelycontrolsneuronalstoreoperatedca2entrythroughfynkinase
AT limdmitry theprionproteinconstitutivelycontrolsneuronalstoreoperatedca2entrythroughfynkinase
AT hillandrewf theprionproteinconstitutivelycontrolsneuronalstoreoperatedca2entrythroughfynkinase
AT sorgatomcatia theprionproteinconstitutivelycontrolsneuronalstoreoperatedca2entrythroughfynkinase
AT bertolialessandro theprionproteinconstitutivelycontrolsneuronalstoreoperatedca2entrythroughfynkinase
AT demarioagnese prionproteinconstitutivelycontrolsneuronalstoreoperatedca2entrythroughfynkinase
AT castellaniangela prionproteinconstitutivelycontrolsneuronalstoreoperatedca2entrythroughfynkinase
AT peggioncaterina prionproteinconstitutivelycontrolsneuronalstoreoperatedca2entrythroughfynkinase
AT massiminomarialina prionproteinconstitutivelycontrolsneuronalstoreoperatedca2entrythroughfynkinase
AT limdmitry prionproteinconstitutivelycontrolsneuronalstoreoperatedca2entrythroughfynkinase
AT hillandrewf prionproteinconstitutivelycontrolsneuronalstoreoperatedca2entrythroughfynkinase
AT sorgatomcatia prionproteinconstitutivelycontrolsneuronalstoreoperatedca2entrythroughfynkinase
AT bertolialessandro prionproteinconstitutivelycontrolsneuronalstoreoperatedca2entrythroughfynkinase