title: Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons.
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.
authors.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;
authors.forename: Hélène
authors.initials: H
authors.lastname: Doucet-Beaupré
authors.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;
authors.forename: Catherine
authors.initials: C
authors.lastname: Gilbert
authors.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;
authors.forename: Marcos Schaan
authors.initials: MS
authors.lastname: Profes
authors.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;
authors.forename: Audrey
authors.initials: A
authors.lastname: Chabrat
authors.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;
authors.forename: Consiglia
authors.initials: C
authors.lastname: Pacelli
authors.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;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Giguère
authors.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;
authors.forename: Véronique
authors.initials: V
authors.lastname: Rioux
authors.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;
authors.forename: Julien
authors.identifier: 0000-0002-1831-5356
authors.initials: J
authors.lastname: Charest
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden;
authors.forename: Qiaolin
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; The Ludwig Institute for Cancer Research, 171 77 Stockholm, Sweden;
authors.forename: Ariadna
authors.initials: A
authors.lastname: Laguna
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden;
authors.forename: Johan
authors.initials: J
authors.lastname: Ericson
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; The Ludwig Institute for Cancer Research, 171 77 Stockholm, Sweden;
authors.forename: Thomas
authors.initials: T
authors.lastname: Perlmann
authors.affiliation: The Francis Crick Institute, London, NW1 2BE, United Kingdom;
authors.forename: Siew-Lan
authors.initials: SL
authors.lastname: Ang
authors.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.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cicchetti
authors.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;
authors.forename: Martin
authors.initials: M
authors.lastname: Parent
authors.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;
authors.forename: Louis-Eric
authors.initials: LE
authors.lastname: Trudeau
authors.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.
authors.forename: Martin
authors.initials: M
authors.lastname: Lévesque
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000235:genetics; D004249:DNA Damage; D059290:Dopaminergic Neurons / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000172:deficiency / Q000235:genetics*; D008636:Mesencephalon / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D066263:Protein Aggregation, Pathological; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: C112149:LIM homeobox transcription factor 1 beta; D060850:LIM-Homeodomain Proteins; C489692:Lmx1a protein, mouse; D014157:Transcription Factors; D051844:alpha-Synuclein
keywords: Parkinson's disease; dopamine neurons; mitochondrial dysfunctions; protein aggregates; transcription factors