title: Coenzyme A corrects pathological defects in human neurons of PANK2-associated neurodegeneration.
abstract: Pantothenate kinase-associated neurodegeneration (PKAN) is an early onset and severely disabling neurodegenerative disease for which no therapy is available. PKAN is caused by mutations in PANK2, which encodes for the mitochondrial enzyme pantothenate kinase 2. Its function is to catalyze the first limiting step of Coenzyme A (CoA) biosynthesis. We generated induced pluripotent stem cells from PKAN patients and showed that their derived neurons exhibited premature death, increased ROS production, mitochondrial dysfunctions-including impairment of mitochondrial iron-dependent biosynthesis-and major membrane excitability defects. CoA supplementation prevented neuronal death and ROS formation by restoring mitochondrial and neuronal functionality. Our findings provide direct evidence that PANK2 malfunctioning is responsible for abnormal phenotypes in human neuronal cells and indicate CoA treatment as a possible therapeutic intervention.
authors: Proteomics of Iron Metabolism Unit, Division of Neuroscience San Raffaele Scientific Institute, Milan, Italy.
authors: Daniel I
authors: DI
authors: Orellana
authors: Proteomics of Iron Metabolism Unit, Division of Neuroscience San Raffaele Scientific Institute, Milan, Italy.
authors: Paolo
authors: P
authors: Santambrogio
authors: Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors: Alicia
authors: A
authors: Rubio
authors: Neuroimmunology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors: Latefa
authors: L
authors: Yekhlef
authors: Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors: Cinzia
authors: C
authors: Cancellieri
authors: Molecular Neurogenetics Unit, Foundation IRCCS-Neurological Institute "Carlo Besta", Milan, Italy.
authors: Sabrina
authors: S
authors: Dusi
authors: Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors: Serena G
authors: SG
authors: Giannelli
authors: Molecular Neurogenetics Unit, Foundation IRCCS-Neurological Institute "Carlo Besta", Milan, Italy.
authors: Paola
authors: P
authors: Venco
authors: Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors: Pietro G
authors: PG
authors: Mazzara
authors: Proteomics of Iron Metabolism Unit, Division of Neuroscience San Raffaele Scientific Institute, Milan, Italy.
authors: Anna
authors: A
authors: Cozzi
authors: Genomic Unit for the Diagnosis of Human Pathologies, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy.
authors: Maurizio
authors: M
authors: Ferrari
authors: Molecular Neurogenetics Unit, Foundation IRCCS-Neurological Institute "Carlo Besta", Milan, Italy.
authors: Barbara
authors: B
authors: Garavaglia
authors: Neuroimmunology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors: Stefano
authors: S
authors: Taverna
authors: Molecular Neurogenetics Unit, Foundation IRCCS-Neurological Institute "Carlo Besta", Milan, Italy.
authors: Valeria
authors: V
authors: Tiranti
authors: Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy Institute of Neuroscience, National Research Council, Milan, Italy.
authors: Vania
authors: V
authors: Broccoli
authors: Proteomics of Iron Metabolism Unit, Division of Neuroscience San Raffaele Scientific Institute, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy levi.sonia@hsr.it.
authors: Sonia
authors: 0000-0002-5092-0847
authors: S
authors: Levi
mesh_terms: D016923:Cell Death; D002478:Cells, Cultured; D003065:Coenzyme A / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D006211:Pantothenate Kinase-Associated Neurodegeneration / Q000503:physiopathology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency*; D039904:Pluripotent Stem Cells / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D003065:Coenzyme A
keywords: 
  PKAN
  ; Coenzyme A; hiPSC; iron; neurodegeneration