Neuronal Ablation of CoA Synthase Causes Motor Deficits, Iron Dyshomeostasis, and Mitochondrial Dysfunctions in a CoPAN Mouse Model
COASY protein-associated neurodegeneration (CoPAN) is a rare but devastating genetic autosomal recessive disorder of inborn error of CoA metabolism, which shares with pantothenate kinase-associated neurodegeneration (PKAN) similar features, such as dystonia, parkinsonian traits, cognitive impairment...
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doaj-1c5c71becdee45d1a8de4927da89ebb62020-12-20T00:01:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-12-01219707970710.3390/ijms21249707Neuronal Ablation of CoA Synthase Causes Motor Deficits, Iron Dyshomeostasis, and Mitochondrial Dysfunctions in a CoPAN Mouse ModelIvano Di Meo0Chiara Cavestro1Silvia Pedretti2Tingting Fu3Simona Ligorio4Antonello Manocchio5Lucrezia Lavermicocca6Paolo Santambrogio7Maddalena Ripamonti8Sonia Levi9Sophie Ayciriex10Nico Mitro11Valeria Tiranti12Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, ItalyUnit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, ItalyDiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, ItalyInstitut des Sciences Analytiques, Univ Lyon, CNRS, Université Claude Bernard Lyon 1, UMR 5280, 5 rue de la Doua, F-69100 Villeurbanne, FranceDiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, ItalyUnit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, ItalyUnit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, ItalyIRCCS San Raffaele Scientific Institute, 20132 Milan, ItalyIRCCS San Raffaele Scientific Institute, 20132 Milan, ItalyIRCCS San Raffaele Scientific Institute, 20132 Milan, ItalyInstitut des Sciences Analytiques, Univ Lyon, CNRS, Université Claude Bernard Lyon 1, UMR 5280, 5 rue de la Doua, F-69100 Villeurbanne, FranceDiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, ItalyUnit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, ItalyCOASY protein-associated neurodegeneration (CoPAN) is a rare but devastating genetic autosomal recessive disorder of inborn error of CoA metabolism, which shares with pantothenate kinase-associated neurodegeneration (PKAN) similar features, such as dystonia, parkinsonian traits, cognitive impairment, axonal neuropathy, and brain iron accumulation. These two disorders are part of the big group of neurodegenerations with brain iron accumulation (NBIA) for which no effective treatment is available at the moment. To date, the lack of a mammalian model, fully recapitulating the human disorder, has prevented the elucidation of pathogenesis and the development of therapeutic approaches. To gain new insights into the mechanisms linking CoA metabolism, iron dyshomeostasis, and neurodegeneration, we generated and characterized the first CoPAN disease mammalian model. Since CoA is a crucial metabolite, constitutive ablation of the <i>Coasy</i> gene is incompatible with life. On the contrary, a conditional neuronal-specific <i>Coasy</i> knock-out mouse model consistently developed a severe early onset neurological phenotype characterized by sensorimotor defects and dystonia-like movements, leading to premature death. For the first time, we highlighted defective brain iron homeostasis, elevation of iron, calcium, and magnesium, together with mitochondrial dysfunction. Surprisingly, total brain CoA levels were unchanged, and no signs of neurodegeneration were present.https://www.mdpi.com/1422-0067/21/24/9707neurodegenerationCoPAN (COASY protein-associated neurodegeneration)NBIA (neurodegeneration with brain iron accumulation)coenzyme Aironmitochondria |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ivano Di Meo Chiara Cavestro Silvia Pedretti Tingting Fu Simona Ligorio Antonello Manocchio Lucrezia Lavermicocca Paolo Santambrogio Maddalena Ripamonti Sonia Levi Sophie Ayciriex Nico Mitro Valeria Tiranti |
spellingShingle |
Ivano Di Meo Chiara Cavestro Silvia Pedretti Tingting Fu Simona Ligorio Antonello Manocchio Lucrezia Lavermicocca Paolo Santambrogio Maddalena Ripamonti Sonia Levi Sophie Ayciriex Nico Mitro Valeria Tiranti Neuronal Ablation of CoA Synthase Causes Motor Deficits, Iron Dyshomeostasis, and Mitochondrial Dysfunctions in a CoPAN Mouse Model International Journal of Molecular Sciences neurodegeneration CoPAN (COASY protein-associated neurodegeneration) NBIA (neurodegeneration with brain iron accumulation) coenzyme A iron mitochondria |
author_facet |
Ivano Di Meo Chiara Cavestro Silvia Pedretti Tingting Fu Simona Ligorio Antonello Manocchio Lucrezia Lavermicocca Paolo Santambrogio Maddalena Ripamonti Sonia Levi Sophie Ayciriex Nico Mitro Valeria Tiranti |
author_sort |
Ivano Di Meo |
title |
Neuronal Ablation of CoA Synthase Causes Motor Deficits, Iron Dyshomeostasis, and Mitochondrial Dysfunctions in a CoPAN Mouse Model |
title_short |
Neuronal Ablation of CoA Synthase Causes Motor Deficits, Iron Dyshomeostasis, and Mitochondrial Dysfunctions in a CoPAN Mouse Model |
title_full |
Neuronal Ablation of CoA Synthase Causes Motor Deficits, Iron Dyshomeostasis, and Mitochondrial Dysfunctions in a CoPAN Mouse Model |
title_fullStr |
Neuronal Ablation of CoA Synthase Causes Motor Deficits, Iron Dyshomeostasis, and Mitochondrial Dysfunctions in a CoPAN Mouse Model |
title_full_unstemmed |
Neuronal Ablation of CoA Synthase Causes Motor Deficits, Iron Dyshomeostasis, and Mitochondrial Dysfunctions in a CoPAN Mouse Model |
title_sort |
neuronal ablation of coa synthase causes motor deficits, iron dyshomeostasis, and mitochondrial dysfunctions in a copan mouse model |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-12-01 |
description |
COASY protein-associated neurodegeneration (CoPAN) is a rare but devastating genetic autosomal recessive disorder of inborn error of CoA metabolism, which shares with pantothenate kinase-associated neurodegeneration (PKAN) similar features, such as dystonia, parkinsonian traits, cognitive impairment, axonal neuropathy, and brain iron accumulation. These two disorders are part of the big group of neurodegenerations with brain iron accumulation (NBIA) for which no effective treatment is available at the moment. To date, the lack of a mammalian model, fully recapitulating the human disorder, has prevented the elucidation of pathogenesis and the development of therapeutic approaches. To gain new insights into the mechanisms linking CoA metabolism, iron dyshomeostasis, and neurodegeneration, we generated and characterized the first CoPAN disease mammalian model. Since CoA is a crucial metabolite, constitutive ablation of the <i>Coasy</i> gene is incompatible with life. On the contrary, a conditional neuronal-specific <i>Coasy</i> knock-out mouse model consistently developed a severe early onset neurological phenotype characterized by sensorimotor defects and dystonia-like movements, leading to premature death. For the first time, we highlighted defective brain iron homeostasis, elevation of iron, calcium, and magnesium, together with mitochondrial dysfunction. Surprisingly, total brain CoA levels were unchanged, and no signs of neurodegeneration were present. |
topic |
neurodegeneration CoPAN (COASY protein-associated neurodegeneration) NBIA (neurodegeneration with brain iron accumulation) coenzyme A iron mitochondria |
url |
https://www.mdpi.com/1422-0067/21/24/9707 |
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