Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration
Identifieur interne : 001104 ( Main/Exploration ); précédent : 001103; suivant : 001105Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration
Auteurs : Benjamin Dehay [France] ; Alfredo Ramirez [Allemagne] ; Marta Martinez-Vicente [Espagne] ; Celine Perier [Espagne] ; Marie-Hélène Canron [France] ; Evelyne Doudnikoff [France] ; Anne Vital [France] ; Miquel Vila [Espagne] ; Christine Klein [Allemagne] ; Erwan Bezard [France]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2012.
English descriptors
- KwdEn :
- MESH :
- chemical , metabolism : Adenosine Triphosphatases.
- enzymology : Parkinson Disease.
- metabolism : Lysosomes, Parkinson Disease.
- pathology : Parkinson Disease.
- Cell Line, Gene Knockdown Techniques, Humans.
Abstract
Parkinson disease (PD) is a progressive neurodegenerative disorder pathologically characterized by the loss of dopaminergic neurons from the substantia nigra pars compacta and the presence, in affected brain regions, of protein inclusions named Lewy bodies (LBs). The
Url:
DOI: 10.1073/pnas.1112368109
PubMed: 22647602
PubMed Central: 3386132
Affiliations:
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Le document en format XML
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last="Dehay">Benjamin Dehay</name><affiliation wicri:level="3"><nlm:aff id="aff1">Insitute of Neurodegenerative Diseases, University of Bordeaux Segalen, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076 Bordeaux, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Insitute of Neurodegenerative Diseases, University of Bordeaux Segalen, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076 Bordeaux</wicri:regionArea><placeName><region type="region" nuts="2">Nouvelle-Aquitaine</region><region type="old region" nuts="2">Aquitaine</region><settlement type="city">Bordeaux</settlement></placeName></affiliation></author><author><name sortKey="Ramirez, Alfredo" sort="Ramirez, Alfredo" uniqKey="Ramirez A" first="Alfredo" last="Ramirez">Alfredo Ramirez</name><affiliation wicri:level="1"><nlm:aff id="aff2">Section of Clinical and Molecular Neurogenetics, Department of Neurology,<institution>University of Lubeck</institution>, 23538 Lubeck,<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="Martinez Vicente, Marta" sort="Martinez Vicente, Marta" uniqKey="Martinez Vicente M" first="Marta" last="Martinez-Vicente">Marta Martinez-Vicente</name><affiliation wicri:level="1"><nlm:aff id="aff3">Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute,<institution>Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas</institution>, 08035 Barcelona,<country>Spain</country>;</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Perier, Celine" sort="Perier, Celine" uniqKey="Perier C" first="Celine" last="Perier">Celine Perier</name><affiliation wicri:level="1"><nlm:aff id="aff3">Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute,<institution>Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas</institution>, 08035 Barcelona,<country>Spain</country>;</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Canron, Marie Helene" sort="Canron, Marie Helene" uniqKey="Canron M" first="Marie-Hélène" last="Canron">Marie-Hélène Canron</name><affiliation wicri:level="3"><nlm:aff id="aff1">Insitute of Neurodegenerative Diseases, University of Bordeaux Segalen, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076 Bordeaux, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Insitute of Neurodegenerative Diseases, University of Bordeaux Segalen, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076 Bordeaux</wicri:regionArea><placeName><region type="region" nuts="2">Nouvelle-Aquitaine</region><region type="old region" nuts="2">Aquitaine</region><settlement type="city">Bordeaux</settlement></placeName></affiliation></author><author><name sortKey="Doudnikoff, Evelyne" sort="Doudnikoff, Evelyne" uniqKey="Doudnikoff E" first="Evelyne" last="Doudnikoff">Evelyne Doudnikoff</name><affiliation wicri:level="3"><nlm:aff id="aff1">Insitute of Neurodegenerative Diseases, University of Bordeaux Segalen, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076 Bordeaux, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Insitute of Neurodegenerative Diseases, University of Bordeaux Segalen, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076 Bordeaux</wicri:regionArea><placeName><region type="region" nuts="2">Nouvelle-Aquitaine</region><region type="old region" nuts="2">Aquitaine</region><settlement type="city">Bordeaux</settlement></placeName></affiliation></author><author><name sortKey="Vital, Anne" sort="Vital, Anne" uniqKey="Vital A" first="Anne" last="Vital">Anne Vital</name><affiliation wicri:level="3"><nlm:aff id="aff1">Insitute of Neurodegenerative Diseases, University of Bordeaux Segalen, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076 Bordeaux, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Insitute of Neurodegenerative Diseases, University of Bordeaux Segalen, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076 Bordeaux</wicri:regionArea><placeName><region type="region" nuts="2">Nouvelle-Aquitaine</region><region type="old region" nuts="2">Aquitaine</region><settlement type="city">Bordeaux</settlement></placeName></affiliation></author><author><name sortKey="Vila, Miquel" sort="Vila, Miquel" uniqKey="Vila M" first="Miquel" last="Vila">Miquel Vila</name><affiliation wicri:level="1"><nlm:aff id="aff3">Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute,<institution>Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas</institution>, 08035 Barcelona,<country>Spain</country>;</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="aff4">Department of Biochemistry and Molecular Biology,<institution>Autonomous University of Barcelona</institution>, 08193 Bellaterra, Barcelona,<country>Spain</country></nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Catalan Institution for Research and Advanced Studies</institution>, 08010 Barcelona,<country>Spain</country></nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Klein, Christine" sort="Klein, Christine" uniqKey="Klein C" first="Christine" last="Klein">Christine Klein</name><affiliation wicri:level="1"><nlm:aff id="aff2">Section of Clinical and Molecular Neurogenetics, Department of Neurology,<institution>University of Lubeck</institution>, 23538 Lubeck,<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="Bezard, Erwan" sort="Bezard, Erwan" uniqKey="Bezard E" first="Erwan" last="Bezard">Erwan Bezard</name><affiliation wicri:level="3"><nlm:aff id="aff1">Insitute of Neurodegenerative Diseases, University of Bordeaux Segalen, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076 Bordeaux, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Insitute of Neurodegenerative Diseases, University of Bordeaux Segalen, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076 Bordeaux</wicri:regionArea><placeName><region type="region" nuts="2">Nouvelle-Aquitaine</region><region type="old region" nuts="2">Aquitaine</region><settlement type="city">Bordeaux</settlement></placeName></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adenosine Triphosphatases (metabolism)</term><term>Cell Line</term><term>Gene Knockdown Techniques</term><term>Humans</term><term>Lysosomes (metabolism)</term><term>Parkinson Disease (enzymology)</term><term>Parkinson Disease (metabolism)</term><term>Parkinson Disease (pathology)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Adenosine Triphosphatases</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Lysosomes</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line</term><term>Gene Knockdown Techniques</term><term>Humans</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Parkinson disease (PD) is a progressive neurodegenerative disorder pathologically characterized by the loss of dopaminergic neurons from the substantia nigra pars compacta and the presence, in affected brain regions, of protein inclusions named Lewy bodies (LBs). The <italic>ATP13A2</italic> gene (locus PARK9) encodes the protein ATP13A2, a lysosomal type 5 P-type ATPase that is linked to autosomal recessive familial parkinsonism. The physiological function of ATP13A2, and hence its role in PD, remains to be elucidated. Here, we show that PD-linked mutations in ATP13A2 lead to several lysosomal alterations in ATP13A2 PD patient-derived fibroblasts, including impaired lysosomal acidification, decreased proteolytic processing of lysosomal enzymes, reduced degradation of lysosomal substrates, and diminished lysosomal-mediated clearance of autophagosomes. Similar alterations are observed in stable ATP13A2-knockdown dopaminergic cell lines, which are associated with cell death. Restoration of ATP13A2 levels in ATP13A2-mutant/depleted cells restores lysosomal function and attenuates cell death. Relevant to PD, ATP13A2 levels are decreased in dopaminergic nigral neurons from patients with PD, in which ATP13A2 mostly accumulates within Lewy bodies. Our results unravel an instrumental role of ATP13A2 deficiency on lysosomal function and cell viability and demonstrate the feasibility and therapeutic potential of modulating ATP13A2 levels in the context of PD.</p></div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Espagne</li><li>France</li></country><region><li>Aquitaine</li><li>Nouvelle-Aquitaine</li></region><settlement><li>Bordeaux</li></settlement></list><tree><country name="France"><region name="Nouvelle-Aquitaine"><name sortKey="Dehay, Benjamin" sort="Dehay, Benjamin" uniqKey="Dehay B" first="Benjamin" last="Dehay">Benjamin Dehay</name></region><name sortKey="Bezard, Erwan" sort="Bezard, Erwan" uniqKey="Bezard E" first="Erwan" last="Bezard">Erwan Bezard</name><name sortKey="Canron, Marie Helene" sort="Canron, Marie Helene" uniqKey="Canron M" first="Marie-Hélène" last="Canron">Marie-Hélène Canron</name><name sortKey="Doudnikoff, Evelyne" sort="Doudnikoff, Evelyne" uniqKey="Doudnikoff E" first="Evelyne" last="Doudnikoff">Evelyne Doudnikoff</name><name sortKey="Vital, Anne" sort="Vital, Anne" uniqKey="Vital A" first="Anne" last="Vital">Anne Vital</name></country><country name="Allemagne"><noRegion><name sortKey="Ramirez, Alfredo" sort="Ramirez, Alfredo" uniqKey="Ramirez A" first="Alfredo" last="Ramirez">Alfredo Ramirez</name></noRegion><name sortKey="Klein, Christine" sort="Klein, Christine" uniqKey="Klein C" first="Christine" last="Klein">Christine Klein</name></country><country name="Espagne"><noRegion><name sortKey="Martinez Vicente, Marta" sort="Martinez Vicente, Marta" uniqKey="Martinez Vicente M" first="Marta" last="Martinez-Vicente">Marta Martinez-Vicente</name></noRegion><name sortKey="Perier, Celine" sort="Perier, Celine" uniqKey="Perier C" first="Celine" last="Perier">Celine Perier</name><name sortKey="Vila, Miquel" sort="Vila, Miquel" uniqKey="Vila M" first="Miquel" last="Vila">Miquel Vila</name><name sortKey="Vila, Miquel" sort="Vila, Miquel" uniqKey="Vila M" first="Miquel" last="Vila">Miquel Vila</name><name sortKey="Vila, Miquel" sort="Vila, Miquel" uniqKey="Vila M" first="Miquel" last="Vila">Miquel Vila</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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