The Ca2+/Mn2+ ion-pump PMR1 links elevation of cytosolic Ca2+ levels to α-synuclein toxicity in Parkinson's disease models
Identifieur interne : 000011 ( Pmc/Curation ); précédent : 000010; suivant : 000012The Ca2+/Mn2+ ion-pump PMR1 links elevation of cytosolic Ca2+ levels to α-synuclein toxicity in Parkinson's disease models
Auteurs : S. Büttner [Autriche] ; L. Faes [Belgique] ; W N Reichelt [Autriche] ; F. Broeskamp [Autriche] ; L. Habernig [Autriche] ; S. Benke [Autriche] ; N. Kourtis [Grèce] ; D. Ruli [Autriche] ; D. Carmona-Gutierrez [Autriche] ; T. Eisenberg [Autriche] ; P. D'Hooge [Belgique] ; R. Ghillebert [Belgique] ; V. Franssens [Belgique] ; A. Harger [Autriche] ; T R Pieber [Autriche] ; P. Freudenberger [Autriche] ; G. Kroemer [France] ; S J Sigrist [Allemagne] ; J. Winderickx [Belgique] ; G. Callewaert [Belgique] ; N. Tavernarakis [Grèce] ; F. Madeo [Autriche]Source :
- Cell Death and Differentiation [ 1350-9047 ] ; 2012.
Abstract
Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons, which arises from a yet elusive concurrence between genetic and environmental factors. The protein
Url:
DOI: 10.1038/cdd.2012.142
PubMed: 23154387
PubMed Central: 3569987
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The Ca<sup>2+</sup>/Mn<sup>2+</sup> ion-pump PMR1 links elevation of cytosolic Ca<sup>2+</sup> levels to <italic>α</italic>-synuclein toxicity in Parkinson's disease models</title><author><name sortKey="Buttner, S" sort="Buttner, S" uniqKey="Buttner S" first="S" last="Büttner">S. Büttner</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Faes, L" sort="Faes, L" uniqKey="Faes L" first="L" last="Faes">L. Faes</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Research Group Neurodegeneration; Katholieke Universiteit Leuven Campus Kortrijk</institution>, Kortrijk,<country>Belgium</country></nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Functional Biology; Katholieke Universiteit Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Reichelt, W N" sort="Reichelt, W N" uniqKey="Reichelt W" first="W N" last="Reichelt">W N Reichelt</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Broeskamp, F" sort="Broeskamp, F" uniqKey="Broeskamp F" first="F" last="Broeskamp">F. 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Benke</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kourtis, N" sort="Kourtis, N" uniqKey="Kourtis N" first="N" last="Kourtis">N. Kourtis</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Institute of Molecular Biology and Biotechnology; Foundation for Research and Technology-Hellas</institution>, Crete,<country>Greece</country></nlm:aff><country xml:lang="fr">Grèce</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ruli, D" sort="Ruli, D" uniqKey="Ruli D" first="D" last="Ruli">D. Ruli</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Carmona Gutierrez, D" sort="Carmona Gutierrez, D" uniqKey="Carmona Gutierrez D" first="D" last="Carmona-Gutierrez">D. Carmona-Gutierrez</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Eisenberg, T" sort="Eisenberg, T" uniqKey="Eisenberg T" first="T" last="Eisenberg">T. Eisenberg</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="D Hooge, P" sort="D Hooge, P" uniqKey="D Hooge P" first="P" last="D'Hooge">P. D'Hooge</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Research Group Neurodegeneration; Katholieke Universiteit Leuven Campus Kortrijk</institution>, Kortrijk,<country>Belgium</country></nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ghillebert, R" sort="Ghillebert, R" uniqKey="Ghillebert R" first="R" last="Ghillebert">R. Ghillebert</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Functional Biology; Katholieke Universiteit Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Franssens, V" sort="Franssens, V" uniqKey="Franssens V" first="V" last="Franssens">V. Franssens</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Functional Biology; Katholieke Universiteit Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Harger, A" sort="Harger, A" uniqKey="Harger A" first="A" last="Harger">A. Harger</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Department of Internal Medicine, Medical University Graz</institution>, Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Pieber, T R" sort="Pieber, T R" uniqKey="Pieber T" first="T R" last="Pieber">T R Pieber</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Department of Internal Medicine, Medical University Graz</institution>, Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Freudenberger, P" sort="Freudenberger, P" uniqKey="Freudenberger P" first="P" last="Freudenberger">P. Freudenberger</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kroemer, G" sort="Kroemer, G" uniqKey="Kroemer G" first="G" last="Kroemer">G. Kroemer</name><affiliation wicri:level="1"><nlm:aff id="aff6"><institution>INSERM, U848</institution>, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff7"><institution>Metabolomics Platform, Institut Gustave Roussy</institution>, Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff8"><institution>Centre de Recherche des Cordeliers</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff9"><institution>Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff10"><institution>Université Paris Descartes, Sorbonne Paris Cité</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sigrist, S J" sort="Sigrist, S J" uniqKey="Sigrist S" first="S J" last="Sigrist">S J Sigrist</name><affiliation wicri:level="1"><nlm:aff id="aff11"><institution>Institute for Biology/Genetics; Freie Universität Berlin</institution>; Berlin,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Winderickx, J" sort="Winderickx, J" uniqKey="Winderickx J" first="J" last="Winderickx">J. Winderickx</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Functional Biology; Katholieke Universiteit Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Callewaert, G" sort="Callewaert, G" uniqKey="Callewaert G" first="G" last="Callewaert">G. Callewaert</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Research Group Neurodegeneration; Katholieke Universiteit Leuven Campus Kortrijk</institution>, Kortrijk,<country>Belgium</country></nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Tavernarakis, N" sort="Tavernarakis, N" uniqKey="Tavernarakis N" first="N" last="Tavernarakis">N. Tavernarakis</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Institute of Molecular Biology and Biotechnology; Foundation for Research and Technology-Hellas</institution>, Crete,<country>Greece</country></nlm:aff><country xml:lang="fr">Grèce</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Madeo, F" sort="Madeo, F" uniqKey="Madeo F" first="F" last="Madeo">F. Madeo</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23154387</idno><idno type="pmc">3569987</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569987</idno><idno type="RBID">PMC:3569987</idno><idno type="doi">10.1038/cdd.2012.142</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">000011</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000011</idno><idno type="wicri:Area/Pmc/Curation">000011</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000011</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The Ca<sup>2+</sup>/Mn<sup>2+</sup> ion-pump PMR1 links elevation of cytosolic Ca<sup>2+</sup> levels to <italic>α</italic>-synuclein toxicity in Parkinson's disease models</title><author><name sortKey="Buttner, S" sort="Buttner, S" uniqKey="Buttner S" first="S" last="Büttner">S. Büttner</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Faes, L" sort="Faes, L" uniqKey="Faes L" first="L" last="Faes">L. Faes</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Research Group Neurodegeneration; Katholieke Universiteit Leuven Campus Kortrijk</institution>, Kortrijk,<country>Belgium</country></nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Functional Biology; Katholieke Universiteit Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Reichelt, W N" sort="Reichelt, W N" uniqKey="Reichelt W" first="W N" last="Reichelt">W N Reichelt</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Broeskamp, F" sort="Broeskamp, F" uniqKey="Broeskamp F" first="F" last="Broeskamp">F. Broeskamp</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Habernig, L" sort="Habernig, L" uniqKey="Habernig L" first="L" last="Habernig">L. Habernig</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Benke, S" sort="Benke, S" uniqKey="Benke S" first="S" last="Benke">S. Benke</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kourtis, N" sort="Kourtis, N" uniqKey="Kourtis N" first="N" last="Kourtis">N. Kourtis</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Institute of Molecular Biology and Biotechnology; Foundation for Research and Technology-Hellas</institution>, Crete,<country>Greece</country></nlm:aff><country xml:lang="fr">Grèce</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ruli, D" sort="Ruli, D" uniqKey="Ruli D" first="D" last="Ruli">D. Ruli</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Carmona Gutierrez, D" sort="Carmona Gutierrez, D" uniqKey="Carmona Gutierrez D" first="D" last="Carmona-Gutierrez">D. Carmona-Gutierrez</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Eisenberg, T" sort="Eisenberg, T" uniqKey="Eisenberg T" first="T" last="Eisenberg">T. Eisenberg</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="D Hooge, P" sort="D Hooge, P" uniqKey="D Hooge P" first="P" last="D'Hooge">P. D'Hooge</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Research Group Neurodegeneration; Katholieke Universiteit Leuven Campus Kortrijk</institution>, Kortrijk,<country>Belgium</country></nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ghillebert, R" sort="Ghillebert, R" uniqKey="Ghillebert R" first="R" last="Ghillebert">R. Ghillebert</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Functional Biology; Katholieke Universiteit Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Franssens, V" sort="Franssens, V" uniqKey="Franssens V" first="V" last="Franssens">V. Franssens</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Functional Biology; Katholieke Universiteit Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Harger, A" sort="Harger, A" uniqKey="Harger A" first="A" last="Harger">A. Harger</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Department of Internal Medicine, Medical University Graz</institution>, Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Pieber, T R" sort="Pieber, T R" uniqKey="Pieber T" first="T R" last="Pieber">T R Pieber</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Department of Internal Medicine, Medical University Graz</institution>, Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Freudenberger, P" sort="Freudenberger, P" uniqKey="Freudenberger P" first="P" last="Freudenberger">P. Freudenberger</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kroemer, G" sort="Kroemer, G" uniqKey="Kroemer G" first="G" last="Kroemer">G. Kroemer</name><affiliation wicri:level="1"><nlm:aff id="aff6"><institution>INSERM, U848</institution>, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff7"><institution>Metabolomics Platform, Institut Gustave Roussy</institution>, Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff8"><institution>Centre de Recherche des Cordeliers</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff9"><institution>Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff10"><institution>Université Paris Descartes, Sorbonne Paris Cité</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sigrist, S J" sort="Sigrist, S J" uniqKey="Sigrist S" first="S J" last="Sigrist">S J Sigrist</name><affiliation wicri:level="1"><nlm:aff id="aff11"><institution>Institute for Biology/Genetics; Freie Universität Berlin</institution>; Berlin,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Winderickx, J" sort="Winderickx, J" uniqKey="Winderickx J" first="J" last="Winderickx">J. Winderickx</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Functional Biology; Katholieke Universiteit Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Callewaert, G" sort="Callewaert, G" uniqKey="Callewaert G" first="G" last="Callewaert">G. Callewaert</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Research Group Neurodegeneration; Katholieke Universiteit Leuven Campus Kortrijk</institution>, Kortrijk,<country>Belgium</country></nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Tavernarakis, N" sort="Tavernarakis, N" uniqKey="Tavernarakis N" first="N" last="Tavernarakis">N. Tavernarakis</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Institute of Molecular Biology and Biotechnology; Foundation for Research and Technology-Hellas</institution>, Crete,<country>Greece</country></nlm:aff><country xml:lang="fr">Grèce</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Madeo, F" sort="Madeo, F" uniqKey="Madeo F" first="F" last="Madeo">F. Madeo</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Cell Death and Differentiation</title><idno type="ISSN">1350-9047</idno><idno type="eISSN">1476-5403</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons, which arises from a yet elusive concurrence between genetic and environmental factors. The protein <italic>α</italic>-synuclein (<italic>α</italic>Syn), the principle toxic effector in PD, has been shown to interfere with neuronal Ca<sup>2+</sup> fluxes, arguing for an involvement of deregulated Ca<sup>2+</sup> homeostasis in this neuronal demise. Here, we identify the Golgi-resident Ca<sup>2+</sup>/Mn<sup>2+</sup> ATPase PMR1 (plasma membrane-related Ca<sup>2+</sup>-ATPase 1) as a phylogenetically conserved mediator of <italic>α</italic>Syn-driven changes in Ca<sup>2+</sup> homeostasis and cytotoxicity. Expression of <italic>α</italic>Syn in yeast resulted in elevated cytosolic Ca<sup>2+</sup> levels and increased cell death, both of which could be inhibited by deletion of PMR1. Accordingly, absence of PMR1 prevented <italic>α</italic>Syn-induced loss of dopaminergic neurons in nematodes and flies. In addition, <italic>α</italic>Syn failed to compromise locomotion and survival of flies when PMR1 was absent. In conclusion, the <italic>α</italic>Syn-driven rise of cytosolic Ca<sup>2+</sup> levels is pivotal for its cytotoxicity and requires PMR1.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Spillantini, Mg" uniqKey="Spillantini M">MG Spillantini</name></author><author><name sortKey="Schmidt, Ml" uniqKey="Schmidt M">ML Schmidt</name></author><author><name sortKey="Lee, Vm" uniqKey="Lee V">VM Lee</name></author><author><name sortKey="Trojanowski, Jq" uniqKey="Trojanowski J">JQ Trojanowski</name></author><author><name sortKey="Jakes, R" uniqKey="Jakes R">R Jakes</name></author><author><name sortKey="Goedert, M" uniqKey="Goedert M">M Goedert</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kruger, R" uniqKey="Kruger R">R Kruger</name></author><author><name sortKey="Kuhn, W" uniqKey="Kuhn W">W Kuhn</name></author><author><name sortKey="Muller, T" uniqKey="Muller T">T Müller</name></author><author><name 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Cell Death Differ</journal-id><journal-id journal-id-type="iso-abbrev">Cell Death Differ</journal-id><journal-title-group><journal-title>Cell Death and Differentiation</journal-title></journal-title-group><issn pub-type="ppub">1350-9047</issn><issn pub-type="epub">1476-5403</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">23154387</article-id><article-id pub-id-type="pmc">3569987</article-id><article-id pub-id-type="pii">cdd2012142</article-id><article-id pub-id-type="doi">10.1038/cdd.2012.142</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Paper</subject></subj-group></article-categories><title-group><article-title>The Ca<sup>2+</sup>/Mn<sup>2+</sup> ion-pump PMR1 links elevation of cytosolic Ca<sup>2+</sup> levels to <italic>α</italic>-synuclein toxicity in Parkinson's disease models</article-title><alt-title alt-title-type="running">PMR1 regulates <italic>α</italic>-synuclein toxicity</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Büttner</surname><given-names>S</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="author-notes" rid="note1"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Faes</surname><given-names>L</given-names></name><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff3">3</xref><xref ref-type="author-notes" rid="note1"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Reichelt</surname><given-names>W N</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="author-notes" rid="note1"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Broeskamp</surname><given-names>F</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Habernig</surname><given-names>L</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Benke</surname><given-names>S</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kourtis</surname><given-names>N</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Ruli</surname><given-names>D</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Carmona-Gutierrez</surname><given-names>D</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Eisenberg</surname><given-names>T</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>D'hooge</surname><given-names>P</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Ghillebert</surname><given-names>R</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Franssens</surname><given-names>V</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Harger</surname><given-names>A</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Pieber</surname><given-names>T R</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Freudenberger</surname><given-names>P</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kroemer</surname><given-names>G</given-names></name><xref ref-type="aff" rid="aff6">6</xref><xref ref-type="aff" rid="aff7">7</xref><xref ref-type="aff" rid="aff8">8</xref><xref ref-type="aff" rid="aff9">9</xref><xref ref-type="aff" rid="aff10">10</xref></contrib><contrib contrib-type="author"><name><surname>Sigrist</surname><given-names>S J</given-names></name><xref ref-type="aff" rid="aff11">11</xref></contrib><contrib contrib-type="author"><name><surname>Winderickx</surname><given-names>J</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Callewaert</surname><given-names>G</given-names></name><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="corresp" rid="caf1">*</xref></contrib><contrib contrib-type="author"><name><surname>Tavernarakis</surname><given-names>N</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Madeo</surname><given-names>F</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="corresp" rid="caf2">*</xref></contrib><aff id="aff1"><label>1</label><institution>Institute of Molecular Biosciences; University of Graz</institution>; Graz,<country>Austria</country></aff><aff id="aff2"><label>2</label><institution>Research Group Neurodegeneration; Katholieke Universiteit Leuven Campus Kortrijk</institution>, Kortrijk,<country>Belgium</country></aff><aff id="aff3"><label>3</label><institution>Functional Biology; Katholieke Universiteit Leuven</institution>, Leuven,<country>Belgium</country></aff><aff id="aff4"><label>4</label><institution>Institute of Molecular Biology and Biotechnology; Foundation for Research and Technology-Hellas</institution>, Crete,<country>Greece</country></aff><aff id="aff5"><label>5</label><institution>Department of Internal Medicine, Medical University Graz</institution>, Graz,<country>Austria</country></aff><aff id="aff6"><label>6</label><institution>INSERM, U848</institution>, 94805 Villejuif,<country>France</country></aff><aff id="aff7"><label>7</label><institution>Metabolomics Platform, Institut Gustave Roussy</institution>, Villejuif,<country>France</country></aff><aff id="aff8"><label>8</label><institution>Centre de Recherche des Cordeliers</institution>, Paris,<country>France</country></aff><aff id="aff9"><label>9</label><institution>Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP</institution>, Paris,<country>France</country></aff><aff id="aff10"><label>10</label><institution>Université Paris Descartes, Sorbonne Paris Cité</institution>, Paris,<country>France</country></aff><aff id="aff11"><label>11</label><institution>Institute for Biology/Genetics; Freie Universität Berlin</institution>; Berlin,<country>Germany</country></aff></contrib-group><author-notes><corresp id="caf1"><label>*</label><institution>Research Group Neurodegeneration; Katholieke Universiteit Leuven Campus Kortrijk</institution>, Kortrijk, <country>Belgium</country>. Tel: +32 5624 6224; Fax: +32 5624 6994; E-mail: <email>Greet.Callewaert@med.kuleuven.be</email></corresp><corresp id="caf2"><label>*</label><institution>Institute of Molecular Biosciences University of Graz</institution>, Humboldtstrasse 50/EG, Graz 8010, <country>Austria</country>. Tel: +43 316 3808878; Fax: +43 316 3809898; E-mail: <email>Frank.Madeo@uni-graz.at</email></corresp><fn fn-type="present-address" id="note1"><label>12</label><p>These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><month>03</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>16</day><month>11</month><year>2012</year></pub-date><pub-date pub-type="pmc-release"><day>1</day><month>3</month><year>2013</year></pub-date><volume>20</volume><issue>3</issue><fpage>465</fpage><lpage>477</lpage><history><date date-type="received"><day>29</day><month>03</month><year>2012</year></date><date date-type="rev-recd"><day>07</day><month>09</month><year>2012</year></date><date date-type="accepted"><day>09</day><month>10</month><year>2012</year></date></history><permissions><copyright-statement>Copyright © 2013 Macmillan Publishers Limited</copyright-statement><copyright-year>2013</copyright-year><copyright-holder>Macmillan Publishers Limited</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/</license-p></license></permissions><abstract><p>Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons, which arises from a yet elusive concurrence between genetic and environmental factors. The protein <italic>α</italic>-synuclein (<italic>α</italic>Syn), the principle toxic effector in PD, has been shown to interfere with neuronal Ca<sup>2+</sup> fluxes, arguing for an involvement of deregulated Ca<sup>2+</sup> homeostasis in this neuronal demise. Here, we identify the Golgi-resident Ca<sup>2+</sup>/Mn<sup>2+</sup> ATPase PMR1 (plasma membrane-related Ca<sup>2+</sup>-ATPase 1) as a phylogenetically conserved mediator of <italic>α</italic>Syn-driven changes in Ca<sup>2+</sup> homeostasis and cytotoxicity. Expression of <italic>α</italic>Syn in yeast resulted in elevated cytosolic Ca<sup>2+</sup> levels and increased cell death, both of which could be inhibited by deletion of PMR1. Accordingly, absence of PMR1 prevented <italic>α</italic>Syn-induced loss of dopaminergic neurons in nematodes and flies. In addition, <italic>α</italic>Syn failed to compromise locomotion and survival of flies when PMR1 was absent. In conclusion, the <italic>α</italic>Syn-driven rise of cytosolic Ca<sup>2+</sup> levels is pivotal for its cytotoxicity and requires PMR1.</p></abstract><kwd-group><kwd>Parkinson's disease models</kwd><kwd><italic>α</italic>-synuclein</kwd><kwd>Ca<sup>2+</sup> homeostasis</kwd><kwd>yeast cell death</kwd><kwd>PMR1</kwd><kwd>dopaminergic neuron loss</kwd></kwd-group></article-meta></front><floats-group><fig id="fig1"><label>Figure 1</label><caption><p>Heterologous expression of <italic>α</italic>Syn elevates basal [Ca<sup>2+</sup>]<sub>cyt</sub> and amplifies transient [Ca<sup>2+</sup>]<sub>cyt</sub> responses in yeast. (<bold>a</bold>) Determination of basal cytosolic Ca<sup>2+</sup> levels using aequorin-based luminescence measurement of WT yeast cells expressing human <italic>α</italic>Syn for indicated time or harbouring the empty vector (Ctrl.). Mean±S.E.M., <italic>n</italic>=8; ***<italic>P</italic><0.001 and **<italic>P</italic><0.01. (<bold>b</bold>) Flow cytometric quantification of oxidative stress indicated by the superoxide-driven conversion of non-fluorescent dihydroethidium to fluorescent ethidium (DHE→Eth.) of WT yeast cells expressing human <italic>α</italic>Syn for indicated time or harbouring the empty vector (Ctrl.). Mean±S.E.M., <italic>n</italic>=8; ***<italic>P</italic><0.001. (<bold>c</bold>) Survival determined by clonogenicity of WT yeast cells expressing human <italic>α</italic>Syn or harbouring the empty vector control for 24 h and 48 h. Cells were plated on YEPD agar plates. Mean±S.E.M., <italic>n</italic>=10; ***<italic>P</italic><0.001. (<bold>d</bold>) Aequorin-equipped yeast cells harbouring the vector control or expressing <italic>α</italic>Syn for 16 h were challenged with 150 mM CaCl<sub>2</sub> and transient [Ca<sup>2+</sup>]<sub>cyt</sub> responses were observed for 70 s. Data was normalized to maximum peak amplitude of control cells. Mean±S.E.M., <italic>n</italic>=6. (<bold>e</bold>) Western blot analysis of <italic>α</italic>Syn expression in WT cells. Cells were harvested at indicated time points after induction of galactose-driven expression. Blots were probed with antibodies directed against FLAG-epitope to detect FLAG-tagged <italic>α</italic>Syn and against glyceraldehyd-3-phosphate dehydrogenase (GAPDH) as loading control. (<bold>f</bold>) Fluorescence microscopic analysis of WT cells expressing GFP-tagged <italic>α</italic>Syn (<italic>α</italic>Syn<sup>GFP</sup>) or harbouring the corresponding vector control (Ctrl.<sup>GFP</sup>) at indicated time points. (<bold>g</bold>) Determination of basal cytosolic Ca<sup>2+</sup> levels using aequorin-based luminescence measurement of yeast cells expressing human <italic>α</italic>Syn or harbouring the empty vector (Ctrl.) after growth for 12 h, 20 h or 24 h on galactose media (promoter induction) supplemented or not with 2 mM ethylene glycol tetraacetic acid (EGTA). Data has been normalized to equally treated vector control cells. Mean±S.E.M., <italic>n</italic>=6; **<italic>P</italic><0.01 and *<italic>P</italic><0.05. (<bold>h</bold>) Flow cytometric quantification of oxidative stress by assessing the ROS-driven conversion of dihydroethidium to ethidium (DHE→Eth) upon expression of <italic>α</italic>Syn for indicated time and supplementation of media with 2 mM EGTA. Mean±S.E.M., <italic>n</italic>=4–8; ***<italic>P</italic><0.001 and **<italic>P</italic><0.01. (<bold>i</bold>) Survival determined by clonogenicity of yeast cells expressing <italic>α</italic>Syn or harbouring the empty vector control for 48 h and supplementation of galactose medium with 2 mM EGTA. Cells were plated on YEPD agar plates. Mean±S.E.M., <italic>n</italic>=12; ***<italic>P</italic><0.001</p></caption><graphic xlink:href="cdd2012142f1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>The antioxidant NAC inhibits <italic>α</italic>Syn cytotoxicity. (<bold>a</bold>) Survival determined by clonogenicity of yeast cells expressing <italic>α</italic>Syn or harbouring the empty vector. Galactose growth medium (for promoter induction) has been supplemented or not with 20 mM or 30 mM NAC as indicated and cells were plated on YEPD agar plates at day 1 and day 2 to determine survival. Mean±S.E.M., <italic>n</italic>=12–18. Significances have been calculated for day 2, with ***<italic>P</italic><0.001 and **<italic>P</italic><0.01. (<bold>b</bold>) Flow cytometric quantification of oxidative stress by assessing the ROS-driven conversion of dihydroethidium to ethidium (DHE→Eth) of cells described in (<bold>a</bold>). Mean±S.E.M., <italic>n</italic>=8. Significances have been calculated for day 2, with ***<italic>P</italic><0.001 and *<italic>P</italic><0.05. (<bold>c</bold>) Representative micrographs of dihydroethidium to ethidium (DHE→Eth) staining of cells expressing <italic>α</italic>Syn or harbouring the empty vector after supplementation of galactose growth medium with 20 mM NAC for 2 days as flow cytometrically quantified in (<bold>b</bold>). (<bold>d</bold>) Determination of basal cytosolic Ca<sup>2+</sup> levels using aequorin-based luminescence measurement of yeast cells expressing <italic>α</italic>Syn or harbouring the empty vector after growth on galactose media supplemented or not with indicated concentrations of NAC for 20 h. Data has been normalized to equally treated vector control cells. Mean±S.E.M., <italic>n</italic>=8; **<italic>P</italic><0.01 and *<italic>P</italic><0.05</p></caption><graphic xlink:href="cdd2012142f2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>The Ca<sup>2+</sup>/Mn<sup>2+</sup> ATPase Pmr1p mediates <italic>α</italic>Syn cytotoxicity. (<bold>a</bold> and <bold>b</bold>) Quantification via fluorescence reader (<bold>a</bold>) and representative micrographs (<bold>b</bold>) of ROS production by assessing the ROS-driven conversion of dihydroethidium to ethidium (DHE→Eth) upon expression of <italic>α</italic>Syn for 24 h in WT yeast cells and indicated deletion mutants. Mean±S.E.M., <italic>n</italic>=8; ***<italic>P</italic><0.001 and **<italic>P</italic><0.01. (<bold>c</bold> and <bold>d</bold>) Flow cytometric quantification (<bold>c</bold>) and representative micrographs (<bold>d</bold>) of externalization of phosphatidylserine (AnnV<sup>+</sup>) and loss of membrane integrity (PI<sup>+</sup>) by Annexin V/PI co-staining of WT cells and indicated deletion mutants expressing <italic>α</italic>Syn for 48 h. Mean±S.E.M., <italic>n</italic>=6; ***<italic>P</italic><0.001. (<bold>e</bold>) Western blot analysis of <italic>α</italic>Syn expression in WT cells and indicated deletion mutants. Blots were probed with antibodies against FLAG-epitope to detect FLAG-tagged <italic>α</italic>Syn and against glyceraldehyd-3-phosphate dehydrogenase (GAPDH) as loading control. (<bold>f</bold>) Survival determined by clonogenicity of WT and Δ<italic>pmr1</italic> yeast cells expressing <italic>α</italic>Syn or harbouring the vector control after 24 h and 48 h of expression on galactose media and plating on YEPD agar plates. Mean±S.E.M., <italic>n</italic>=10; ***<italic>P</italic><0.001. (<bold>g</bold>) Quantification of ROS accumulation (DHE→Eth) in yeast cells in which the promoter region of <italic>PMR1</italic> has been replaced by a doxycycline-repressible promoter (<italic>TetO</italic>-<italic>PMR1</italic>). Doxycycline (Doxy) was added in indicated concentrations and <italic>α</italic>Syn was expressed for 24 h or 48 h. Mean±S.E.M., <italic>n</italic>=8; ***<italic>P</italic><0.001. (<bold>h</bold>) Q-PCR-based quantification of PMR1 mRNA levels in yeast cells described in (<bold>g</bold>) after treatment with 10 <italic>μ</italic>g/ml Doxycycline (Doxy) and <italic>α</italic>Syn expression for 12 h. Data have been normalized to mRNA levels of actin. Means±S.E.M., <italic>n</italic>=3. Asterisks indicate significance between untreated and Doxy-treated cells, ***<italic>P</italic><0.001</p></caption><graphic xlink:href="cdd2012142f3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>Expression of <italic>α</italic>Syn causes a slight upregulation of PMR1 and CCH1 mRNA levels. (<bold>a</bold>) Representative micrographs of yeast cells expressing endogenously GFP-tagged Pmr1p in combination with <italic>α</italic>Syn or corresponding vector control at indicated time points after induction of <italic>α</italic>Syn expression. (<bold>b</bold>) Western blot analysis of cells described in (<bold>a</bold>) at indicated time points after induction of <italic>α</italic>Syn expression. Blots were probed with antibodies against GFP to detect Pmr1p-GFP fusion protein, against FLAG-epitope to detect FLAG-tagged <italic>α</italic>Syn and against glyceraldehyd-3-phosphate dehydrogenase (GAPDH) as loading control. (<bold>c</bold> and <bold>d</bold>) Q-PCR-based quantification of PMR1 mRNA levels (<bold>c</bold>) and of CCH1 and MID1 mRNA levels (<bold>d</bold>) in WT cells expressing <italic>α</italic>Syn or harbouring the empty vector control for 14 h or 24 h, respectively, normalized to actin mRNA levels. Means±S.E.M., <italic>n</italic>=6–9; *<italic>P</italic><0.05. (<bold>e</bold>) Quantification of ROS accumulation (DHE→Eth) in WT yeast cells and indicated deletion mutants expressing <italic>α</italic>Syn for 16 h or 24 h using a fluorescence reader. Mean±S.E.M., <italic>n</italic>=6; ***<italic>P</italic><0.001 and *<italic>P</italic><0.05</p></caption><graphic xlink:href="cdd2012142f4"></graphic></fig><fig id="fig5"><label>Figure 5</label><caption><p>Pmr1p is involved in <italic>α</italic>Syn-induced dysregulation of Ca<sup>2+</sup> homeostasis. (<bold>a</bold>) Aequorin-luminescence-based determination of basal cytosolic Ca<sup>2+</sup> levels in WT cells and indicated deletion mutants expressing <italic>α</italic>Syn for 20 h. Data was normalized to corresponding isogenic vector control. Mean±S.E.M., <italic>n</italic>=12; ***<italic>P</italic><0.001; NS, not significant. (<bold>b</bold>) Aequorin-equipped WT and Δ<italic>pmr1</italic> yeast cells expressing <italic>α</italic>Syn or harbouring the vector control were challenged with 150 mM CaCl<sub>2</sub> and transient [Ca<sup>2+</sup>]<sub>cyt</sub> responses were observed for 50 s. Mean±S.E.M., <italic>n</italic>=6. (<bold>c</bold>) Western blot analysis of aequorin expression and <italic>α</italic>Syn expression in WT cells and indicated deletion mutants. Blots were probed with antibodies directed against aequorin, against FLAG-epitope to detect FLAG-tagged <italic>α</italic>Syn and against glyceraldehyd-3-phosphate dehydrogenase (GAPDH) as loading control. (<bold>d</bold>) Aequorin-equipped WT and Δ<italic>pmr1</italic> cells constitutively expressing <italic>α</italic>Syn (using the expression vector pGGE181) or harbouring the empty pGGE181 vector (Ctrl.) were starved for glucose, supplemented with low doses of Ca<sup>2+</sup> (10 mM) and subsequently challenged with 80 mM glucose. Transient [Ca<sup>2+</sup>]<sub>cyt</sub> responses were monitored. Data represent average recordings, <italic>n</italic>≥9. (<bold>e</bold>) Maximum [Ca<sup>2+</sup>]<sub>cyt</sub> peak amplitude after addition of 80 mM glucose as depicted in (<bold>d</bold>) in aequorin-equipped WT cells and indicated deletion mutants upon expression of <italic>α</italic>Syn. Mean±S.E.M., <italic>n</italic>≥9; ***<italic>P</italic><0.001; NS, not significant</p></caption><graphic xlink:href="cdd2012142f5"></graphic></fig><fig id="fig6"><label>Figure 6</label><caption><p>Expression of Pmr1p restores <italic>α</italic>Syn cytotoxicity and supresses manganese toxicity of <italic>PMR1</italic>-deficient cells. (<bold>a</bold>) Spotting assays of WT and Δ<italic>pmr1</italic> yeast cells expressing <italic>α</italic>Syn or harbouring the vector control. Cells were grown for 24 h in galactose media and spotted in fivefold serial dilutions onto glucose (<italic>α</italic>Syn expression repressed) and galactose (<italic>α</italic>Syn expression induced) agar plates supplemented or not with 2 mM or 4 mM Mn<sup>2+</sup>, respectively. (<bold>b</bold>) Spotting assays of WT and Δ<italic>pmr1</italic> yeast cells expressing either <italic>α</italic>Syn or Pmr1p alone or in combination or harbouring the corresponding vector controls. Cells were grown for 24 h in galactose media and spotted in fivefold serial dilutions onto glucose (Pmr1p and <italic>α</italic>Syn expression repressed) and galactose (Pmr1p and <italic>α</italic>Syn expression induced) agar plates supplemented or not with 4 mM Mn<sup>2+</sup>. (<bold>c</bold>) Quantification of clonogenic survival of cells described in (<bold>b</bold>) after plating on galactose agar plates supplemented or not with 4 mM Mn<sup>2+</sup>. Both Pmr1p as well as <italic>α</italic>Syn expression are driven by a galactose promoter. Mean±S.E.M., <italic>n</italic>=8–12; ***<italic>P</italic><0.001 and **<italic>P</italic><0.01; NS, not significant. Unless otherwise specified, asterisks indicate significances to similarly treated, isogenic control cells harbouring both empty vectors</p></caption><graphic xlink:href="cdd2012142f6"></graphic></fig><fig id="fig7"><label>Figure 7</label><caption><p>Ca<sup>2+</sup> rather than Mn<sup>2+</sup> transport activity of Pmr1p contributes to <italic>α</italic>Syn toxicity. (<bold>a</bold>) Spotting assays of WT and Δ<italic>pmr1</italic> yeast cells expressing either Pmr1p or the point mutants Pmr1p<sup>D53A</sup> and Pmr1p<sup>Q783A</sup> alone or in combination with <italic>α</italic>Syn. Cells were grown for 24 h in galactose media and spotted in fivefold serial dilutions onto glucose (Pmr1p and <italic>α</italic>Syn expression repressed) and galactose (Pmr1p and <italic>α</italic>Syn expression induced) plates supplemented or not with 1 mM and 4 mM Mn<sup>2+</sup>. (<bold>b</bold>) Cells described in (<bold>a</bold>) were subjected to clonogenic survival plating on galactose plates supplemented or not with 1 mM Mn<sup>2+</sup>. Survival has been normalized to WT cells harbouring both empty vectors plated on galactose plates without manganese. Mean±S.E.M., <italic>n</italic>=12–16. (<bold>c</bold>) Western blot analysis of Pmr1p, Pmr1p<sup>D53A</sup> and Pmr1p<sup>Q783A</sup> overexpression as well as of <italic>α</italic>Syn expression in WT and Δ<italic>pmr1</italic> yeast cells. Blots were probed with antibodies directed against FLAG-epitope to detect FLAG-tagged Pmr1p variants and <italic>α</italic>Syn and against glyceraldehyd-3-phosphate dehydrogenase (GAPDH) as loading control</p></caption><graphic xlink:href="cdd2012142f7"></graphic></fig><fig id="fig8"><label>Figure 8</label><caption><p>PMR1 is critical for <italic>α</italic>Syn neurotoxicity in nematodes and flies. (<bold>a</bold>) Survival of <italic>C. elegans</italic> dopaminergic neurons in WT or PMR-1-deficient (<italic>pmr-1(tm1840)</italic>) animals expressing GFP and <italic>α</italic>-Syn. Mean±S.E.M., <italic>n</italic>>250 individual animals; ***<italic>P</italic><0.001. (<bold>b</bold>) Fluorescence-based quantification of cytoplasmic Ca<sup>2+</sup> levels in WT or PMR-1-deficient (<italic>pmr-1(tm1840)</italic>) nematodes expressing the Ca<sup>2+</sup> indicator GCaMP2.0 and <italic>α</italic>-Syn. Mean±S.E.M., <italic>n</italic>>150 dopaminergic neurons. ***<italic>P</italic><0.001. (<bold>c</bold> and <bold>d</bold>) Survival of male (<bold>c</bold>) and female (<bold>d</bold>) WT flies and of flies either expressing human <italic>α</italic>Syn or an RNAi depleting SPoCk (the Drosophila homologue of PMR1) or both (driven by <italic>elav-GAL4</italic>) upon supplementation of food (10% sucrose) with 20 mM Mn<sup>2+</sup>. Means±S.E.M., <italic>n</italic>=12–20 with 35–40 flies per experiment; ***<italic>P</italic><0.001. (<bold>e</bold>) Immunoblot analysis of brain lysats obtained from flies expressing human <italic>α</italic>Syn driven by <italic>elav-GAL4</italic> with or without co-expression of an RNAi-depleting SPoCk using antibodies directed against human <italic>α</italic>Syn or Drosophila <italic>α</italic>-tubulin as loading control. (<bold>f</bold>) Climbing activity of female flies described in (<bold>d</bold>) after 24 h of Mn<sup>2+</sup> treatment. Means±S.E.M., <italic>n</italic>=6–10 with 8 flies per experiment; ***<italic>P</italic><0.001 and *<italic>P</italic><0.05. (<bold>g</bold> and <bold>h</bold>) Total count of tyrosine hydroxylase (TH)-immunoreactive dopaminergic neurons (<bold>g</bold>) in the DM, PM and DL1 brain clusters of female flies expressing <italic>α</italic>Syn alone or in combination with an RNAi-depleting SPoCk after treatment with Mn<sup>2+</sup> for 96 h. Representative confocal microscopy images of dissected brains immunostained for TH and for Bruchpilot (BRP<sup>Nc82</sup>) to visualize brain structure are shown in (<bold>h</bold>). Neuronal counts were quantified by inspection of the individual planes of the z-stack. Means±S.E.M., <italic>n</italic>=5–10; **<italic>P</italic><0.01 and *<italic>P</italic><0.05</p></caption><graphic xlink:href="cdd2012142f8"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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