title: Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson's-like movement disorder.
abstract: Mitophagy is a specialized form of autophagy that selectively disposes of dysfunctional mitochondria. Delineating the molecular regulation of mitophagy is of great importance because defects in this process lead to a variety of mitochondrial diseases. Here we report that mice deficient for the mitochondrial protein, phosphoglycerate mutase family member 5 (PGAM5), displayed a Parkinson's-like movement phenotype. We determined biochemically that PGAM5 is required for the stabilization of the mitophagy-inducing protein PINK1 on damaged mitochondria. Loss of PGAM5 disables PINK1-mediated mitophagy in vitro and leads to dopaminergic neurodegeneration and mild dopamine loss in vivo. Our data indicate that PGAM5 is a regulator of mitophagy essential for mitochondrial turnover and serves a cytoprotective function in dopaminergic neurons in vivo. Moreover, PGAM5 may provide a molecular link to study mitochondrial homeostasis and the pathogenesis of a movement disorder similar to Parkinson's disease.
authors.affiliation: 1] Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA [2].
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: 1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] Adrienne Helis Malvin Medical Research Foundation, New Orleans, Los Angeles 70130-2685, USA [4].
authors.forename: Senthilkumar S
authors.initials: SS
authors.lastname: Karuppagounder
authors.affiliation: Murine Phenotyping Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Springer
authors.affiliation: Murine Phenotyping Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Michele D
authors.initials: MD
authors.lastname: Allen
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Brittany
authors.initials: B
authors.lastname: Chao
authors.affiliation: Molecular Mechanism of Apoptosis Section, Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] Adrienne Helis Malvin Medical Research Foundation, New Orleans, Los Angeles 70130-2685, USA [4] Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [5] Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.affiliation: 1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] Adrienne Helis Malvin Medical Research Foundation, New Orleans, Los Angeles 70130-2685, USA [4] Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [5] Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA.
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lenardo
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004298:Dopamine / Q000172:deficiency; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics*; D063306:Mitophagy / Q000235:genetics; D009043:Motor Activity; D010302:Parkinson Disease, Secondary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000099202:PTEN-Induced Putative Kinase
chemical_list: D004298:Dopamine; D024101:Mitochondrial Proteins; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases; D011494:Protein Kinases; D034741:RNA, Small Interfering; D000099202:PTEN-Induced Putative Kinase; C570696:PGAM5 protein, mouse