Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons.
Identifieur interne : 000301 ( Main/Exploration ); précédent : 000300; suivant : 000302Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons.
Auteurs : Hélène Doucet-Beaupré [Canada] ; Catherine Gilbert [Canada] ; Marcos Schaan Profes [Canada] ; Audrey Chabrat [Canada] ; Consiglia Pacelli [Canada] ; Nicolas Giguère [Canada] ; Véronique Rioux [Canada] ; Julien Charest [Canada] ; Qiaolin Deng [Suède] ; Ariadna Laguna [Suède] ; Johan Ericson [Suède] ; Thomas Perlmann [Suède] ; Siew-Lan Ang [Royaume-Uni] ; Francesca Cicchetti [Canada] ; Martin Parent [Canada] ; Louis-Eric Trudeau [Canada] ; Martin Lévesque [Canada]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 1091-6490 ] ; 2016.
Abstract
The LIM-homeodomain transcription factors Lmx1a and Lmx1b play critical roles during the development of midbrain dopaminergic progenitors, but their functions in the adult brain remain poorly understood. We show here that sustained expression of Lmx1a and Lmx1b is required for the survival of adult midbrain dopaminergic neurons. Strikingly, inactivation of Lmx1a and Lmx1b recreates cellular features observed in Parkinson's disease. We found that Lmx1a/b control the expression of key genes involved in mitochondrial functions, and their ablation results in impaired respiratory chain activity, increased oxidative stress, and mitochondrial DNA damage. Lmx1a/b deficiency caused axonal pathology characterized by α-synuclein(+) inclusions, followed by a progressive loss of dopaminergic neurons. These results reveal the key role of these transcription factors beyond the early developmental stages and provide mechanistic links between mitochondrial dysfunctions, α-synuclein aggregation, and the survival of dopaminergic neurons.
DOI: 10.1073/pnas.1520387113
PubMed: 27407143
Affiliations:
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Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3</wicri:regionArea><wicri:noRegion>QC G1J 2G3</wicri:noRegion></affiliation></author><author><name sortKey="Profes, Marcos Schaan" sort="Profes, Marcos Schaan" uniqKey="Profes M" first="Marcos Schaan" last="Profes">Marcos Schaan Profes</name><affiliation wicri:level="1"><nlm:affiliation>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; 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Department of Neurosciences, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pharmacology, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada; Department of Neurosciences, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4</wicri:regionArea><wicri:noRegion>QC H3T 1J4</wicri:noRegion></affiliation></author><author><name sortKey="Giguere, Nicolas" sort="Giguere, Nicolas" uniqKey="Giguere N" first="Nicolas" last="Giguère">Nicolas Giguère</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacology, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada; Department of Neurosciences, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pharmacology, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada; Department of Neurosciences, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4</wicri:regionArea><wicri:noRegion>QC H3T 1J4</wicri:noRegion></affiliation></author><author><name sortKey="Rioux, Veronique" sort="Rioux, Veronique" uniqKey="Rioux V" first="Véronique" last="Rioux">Véronique Rioux</name><affiliation wicri:level="1"><nlm:affiliation>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3</wicri:regionArea><wicri:noRegion>QC G1J 2G3</wicri:noRegion></affiliation></author><author><name sortKey="Charest, Julien" sort="Charest, Julien" uniqKey="Charest J" first="Julien" last="Charest">Julien Charest</name><affiliation wicri:level="1"><nlm:affiliation>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3</wicri:regionArea><wicri:noRegion>QC G1J 2G3</wicri:noRegion></affiliation></author><author><name sortKey="Deng, Qiaolin" sort="Deng, Qiaolin" uniqKey="Deng Q" first="Qiaolin" last="Deng">Qiaolin Deng</name><affiliation wicri:level="1"><nlm:affiliation>Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden;</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Laguna, Ariadna" sort="Laguna, Ariadna" uniqKey="Laguna A" first="Ariadna" last="Laguna">Ariadna Laguna</name><affiliation wicri:level="1"><nlm:affiliation>Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; The Ludwig Institute for Cancer Research, 171 77 Stockholm, Sweden;</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; The Ludwig Institute for Cancer Research, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Ericson, Johan" sort="Ericson, Johan" uniqKey="Ericson J" first="Johan" last="Ericson">Johan Ericson</name><affiliation wicri:level="1"><nlm:affiliation>Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden;</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Perlmann, Thomas" sort="Perlmann, Thomas" uniqKey="Perlmann T" first="Thomas" last="Perlmann">Thomas Perlmann</name><affiliation wicri:level="1"><nlm:affiliation>Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; The Ludwig Institute for Cancer Research, 171 77 Stockholm, Sweden;</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; The Ludwig Institute for Cancer Research, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Ang, Siew Lan" sort="Ang, Siew Lan" uniqKey="Ang S" first="Siew-Lan" last="Ang">Siew-Lan Ang</name><affiliation wicri:level="1"><nlm:affiliation>The Francis Crick Institute, London, NW1 2BE, United Kingdom;</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>The Francis Crick Institute, London, NW1 2BE</wicri:regionArea><wicri:noRegion>NW1 2BE</wicri:noRegion></affiliation></author><author><name sortKey="Cicchetti, Francesca" sort="Cicchetti, Francesca" uniqKey="Cicchetti F" first="Francesca" last="Cicchetti">Francesca Cicchetti</name><affiliation wicri:level="1"><nlm:affiliation>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de recherche du Centre Hospitalier Universitaire de Québec, Quebec, QC G1V 4G2, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de recherche du Centre Hospitalier Universitaire de Québec, Quebec, QC G1V 4G2</wicri:regionArea><wicri:noRegion>QC G1V 4G2</wicri:noRegion></affiliation></author><author><name sortKey="Parent, Martin" sort="Parent, Martin" uniqKey="Parent M" first="Martin" last="Parent">Martin Parent</name><affiliation wicri:level="1"><nlm:affiliation>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3</wicri:regionArea><wicri:noRegion>QC G1J 2G3</wicri:noRegion></affiliation></author><author><name sortKey="Trudeau, Louis Eric" sort="Trudeau, Louis Eric" uniqKey="Trudeau L" first="Louis-Eric" last="Trudeau">Louis-Eric Trudeau</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacology, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada; Department of Neurosciences, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pharmacology, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada; Department of Neurosciences, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4</wicri:regionArea><wicri:noRegion>QC H3T 1J4</wicri:noRegion></affiliation></author><author><name sortKey="Levesque, Martin" sort="Levesque, Martin" uniqKey="Levesque M" first="Martin" last="Lévesque">Martin Lévesque</name><affiliation wicri:level="1"><nlm:affiliation>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3, Canada; martin.levesque@fmed.ulaval.ca.</nlm:affiliation><country wicri:rule="url">Canada</country><wicri:regionArea>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3</wicri:regionArea><wicri:noRegion>QC G1J 2G3</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:27407143</idno><idno type="pmid">27407143</idno><idno type="doi">10.1073/pnas.1520387113</idno><idno type="wicri:Area/PubMed/Corpus">000196</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000196</idno><idno type="wicri:Area/PubMed/Curation">000196</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000196</idno><idno type="wicri:Area/PubMed/Checkpoint">000196</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000196</idno><idno type="wicri:Area/Ncbi/Merge">002026</idno><idno type="wicri:Area/Ncbi/Curation">002026</idno><idno type="wicri:Area/Ncbi/Checkpoint">002026</idno><idno type="wicri:Area/Main/Merge">000302</idno><idno type="wicri:Area/Main/Curation">000301</idno><idno type="wicri:Area/Main/Exploration">000301</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons.</title><author><name sortKey="Doucet Beaupre, Helene" sort="Doucet Beaupre, Helene" uniqKey="Doucet Beaupre H" first="Hélène" last="Doucet-Beaupré">Hélène Doucet-Beaupré</name><affiliation wicri:level="1"><nlm:affiliation>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3</wicri:regionArea><wicri:noRegion>QC G1J 2G3</wicri:noRegion></affiliation></author><author><name sortKey="Gilbert, Catherine" sort="Gilbert, Catherine" uniqKey="Gilbert C" first="Catherine" last="Gilbert">Catherine Gilbert</name><affiliation wicri:level="1"><nlm:affiliation>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3</wicri:regionArea><wicri:noRegion>QC G1J 2G3</wicri:noRegion></affiliation></author><author><name sortKey="Profes, Marcos Schaan" sort="Profes, Marcos Schaan" uniqKey="Profes M" first="Marcos Schaan" last="Profes">Marcos Schaan Profes</name><affiliation wicri:level="1"><nlm:affiliation>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3</wicri:regionArea><wicri:noRegion>QC G1J 2G3</wicri:noRegion></affiliation></author><author><name sortKey="Chabrat, Audrey" sort="Chabrat, Audrey" uniqKey="Chabrat A" first="Audrey" last="Chabrat">Audrey Chabrat</name><affiliation wicri:level="1"><nlm:affiliation>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3</wicri:regionArea><wicri:noRegion>QC G1J 2G3</wicri:noRegion></affiliation></author><author><name sortKey="Pacelli, Consiglia" sort="Pacelli, Consiglia" uniqKey="Pacelli C" first="Consiglia" last="Pacelli">Consiglia Pacelli</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacology, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada; Department of Neurosciences, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pharmacology, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada; Department of Neurosciences, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4</wicri:regionArea><wicri:noRegion>QC H3T 1J4</wicri:noRegion></affiliation></author><author><name sortKey="Giguere, Nicolas" sort="Giguere, Nicolas" uniqKey="Giguere N" first="Nicolas" last="Giguère">Nicolas Giguère</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacology, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada; Department of Neurosciences, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pharmacology, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada; Department of Neurosciences, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4</wicri:regionArea><wicri:noRegion>QC H3T 1J4</wicri:noRegion></affiliation></author><author><name sortKey="Rioux, Veronique" sort="Rioux, Veronique" uniqKey="Rioux V" first="Véronique" last="Rioux">Véronique Rioux</name><affiliation wicri:level="1"><nlm:affiliation>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3</wicri:regionArea><wicri:noRegion>QC G1J 2G3</wicri:noRegion></affiliation></author><author><name sortKey="Charest, Julien" sort="Charest, Julien" uniqKey="Charest J" first="Julien" last="Charest">Julien Charest</name><affiliation wicri:level="1"><nlm:affiliation>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3</wicri:regionArea><wicri:noRegion>QC G1J 2G3</wicri:noRegion></affiliation></author><author><name sortKey="Deng, Qiaolin" sort="Deng, Qiaolin" uniqKey="Deng Q" first="Qiaolin" last="Deng">Qiaolin Deng</name><affiliation wicri:level="1"><nlm:affiliation>Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden;</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Laguna, Ariadna" sort="Laguna, Ariadna" uniqKey="Laguna A" first="Ariadna" last="Laguna">Ariadna Laguna</name><affiliation wicri:level="1"><nlm:affiliation>Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; The Ludwig Institute for Cancer Research, 171 77 Stockholm, Sweden;</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; The Ludwig Institute for Cancer Research, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Ericson, Johan" sort="Ericson, Johan" uniqKey="Ericson J" first="Johan" last="Ericson">Johan Ericson</name><affiliation wicri:level="1"><nlm:affiliation>Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden;</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Perlmann, Thomas" sort="Perlmann, Thomas" uniqKey="Perlmann T" first="Thomas" last="Perlmann">Thomas Perlmann</name><affiliation wicri:level="1"><nlm:affiliation>Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; The Ludwig Institute for Cancer Research, 171 77 Stockholm, Sweden;</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; The Ludwig Institute for Cancer Research, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Ang, Siew Lan" sort="Ang, Siew Lan" uniqKey="Ang S" first="Siew-Lan" last="Ang">Siew-Lan Ang</name><affiliation wicri:level="1"><nlm:affiliation>The Francis Crick Institute, London, NW1 2BE, United Kingdom;</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>The Francis Crick Institute, London, NW1 2BE</wicri:regionArea><wicri:noRegion>NW1 2BE</wicri:noRegion></affiliation></author><author><name sortKey="Cicchetti, Francesca" sort="Cicchetti, Francesca" uniqKey="Cicchetti F" first="Francesca" last="Cicchetti">Francesca Cicchetti</name><affiliation wicri:level="1"><nlm:affiliation>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de recherche du Centre Hospitalier Universitaire de Québec, Quebec, QC G1V 4G2, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de recherche du Centre Hospitalier Universitaire de Québec, Quebec, QC G1V 4G2</wicri:regionArea><wicri:noRegion>QC G1V 4G2</wicri:noRegion></affiliation></author><author><name sortKey="Parent, Martin" sort="Parent, Martin" uniqKey="Parent M" first="Martin" last="Parent">Martin Parent</name><affiliation wicri:level="1"><nlm:affiliation>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3</wicri:regionArea><wicri:noRegion>QC G1J 2G3</wicri:noRegion></affiliation></author><author><name sortKey="Trudeau, Louis Eric" sort="Trudeau, Louis Eric" uniqKey="Trudeau L" first="Louis-Eric" last="Trudeau">Louis-Eric Trudeau</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacology, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada; Department of Neurosciences, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada;</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pharmacology, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada; Department of Neurosciences, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4</wicri:regionArea><wicri:noRegion>QC H3T 1J4</wicri:noRegion></affiliation></author><author><name sortKey="Levesque, Martin" sort="Levesque, Martin" uniqKey="Levesque M" first="Martin" last="Lévesque">Martin Lévesque</name><affiliation wicri:level="1"><nlm:affiliation>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3, Canada; martin.levesque@fmed.ulaval.ca.</nlm:affiliation><country wicri:rule="url">Canada</country><wicri:regionArea>Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Quebec QC G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec, QC G1J 2G3</wicri:regionArea><wicri:noRegion>QC G1J 2G3</wicri:noRegion></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="eISSN">1091-6490</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The LIM-homeodomain transcription factors Lmx1a and Lmx1b play critical roles during the development of midbrain dopaminergic progenitors, but their functions in the adult brain remain poorly understood. We show here that sustained expression of Lmx1a and Lmx1b is required for the survival of adult midbrain dopaminergic neurons. Strikingly, inactivation of Lmx1a and Lmx1b recreates cellular features observed in Parkinson's disease. We found that Lmx1a/b control the expression of key genes involved in mitochondrial functions, and their ablation results in impaired respiratory chain activity, increased oxidative stress, and mitochondrial DNA damage. Lmx1a/b deficiency caused axonal pathology characterized by α-synuclein(+) inclusions, followed by a progressive loss of dopaminergic neurons. These results reveal the key role of these transcription factors beyond the early developmental stages and provide mechanistic links between mitochondrial dysfunctions, α-synuclein aggregation, and the survival of dopaminergic neurons.</div></front></TEI><affiliations><list><country><li>Canada</li><li>Royaume-Uni</li><li>Suède</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Doucet Beaupre, Helene" sort="Doucet Beaupre, Helene" uniqKey="Doucet Beaupre H" first="Hélène" last="Doucet-Beaupré">Hélène Doucet-Beaupré</name></noRegion><name sortKey="Chabrat, Audrey" sort="Chabrat, Audrey" uniqKey="Chabrat A" first="Audrey" last="Chabrat">Audrey Chabrat</name><name sortKey="Charest, Julien" sort="Charest, Julien" uniqKey="Charest J" first="Julien" last="Charest">Julien Charest</name><name sortKey="Cicchetti, Francesca" sort="Cicchetti, Francesca" uniqKey="Cicchetti F" first="Francesca" last="Cicchetti">Francesca Cicchetti</name><name sortKey="Giguere, Nicolas" sort="Giguere, Nicolas" uniqKey="Giguere N" first="Nicolas" last="Giguère">Nicolas Giguère</name><name sortKey="Gilbert, Catherine" sort="Gilbert, Catherine" uniqKey="Gilbert C" first="Catherine" last="Gilbert">Catherine Gilbert</name><name sortKey="Levesque, Martin" sort="Levesque, Martin" uniqKey="Levesque M" first="Martin" last="Lévesque">Martin Lévesque</name><name sortKey="Pacelli, Consiglia" sort="Pacelli, Consiglia" uniqKey="Pacelli C" first="Consiglia" last="Pacelli">Consiglia Pacelli</name><name sortKey="Parent, Martin" sort="Parent, Martin" uniqKey="Parent M" first="Martin" last="Parent">Martin Parent</name><name sortKey="Profes, Marcos Schaan" sort="Profes, Marcos Schaan" uniqKey="Profes M" first="Marcos Schaan" last="Profes">Marcos Schaan Profes</name><name sortKey="Rioux, Veronique" sort="Rioux, Veronique" uniqKey="Rioux V" first="Véronique" last="Rioux">Véronique Rioux</name><name sortKey="Trudeau, Louis Eric" sort="Trudeau, Louis Eric" uniqKey="Trudeau L" first="Louis-Eric" last="Trudeau">Louis-Eric Trudeau</name></country><country name="Suède"><noRegion><name sortKey="Deng, Qiaolin" sort="Deng, Qiaolin" uniqKey="Deng Q" first="Qiaolin" last="Deng">Qiaolin Deng</name></noRegion><name sortKey="Ericson, Johan" sort="Ericson, Johan" uniqKey="Ericson J" first="Johan" last="Ericson">Johan Ericson</name><name sortKey="Laguna, Ariadna" sort="Laguna, Ariadna" uniqKey="Laguna A" first="Ariadna" last="Laguna">Ariadna Laguna</name><name sortKey="Perlmann, Thomas" sort="Perlmann, Thomas" uniqKey="Perlmann T" first="Thomas" last="Perlmann">Thomas Perlmann</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Ang, Siew Lan" sort="Ang, Siew Lan" uniqKey="Ang S" first="Siew-Lan" last="Ang">Siew-Lan Ang</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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