1. Coenzyme A corrects pathological defects in human neurons of PANK2-associated neurodegeneration.
- Author
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Orellana DI, Santambrogio P, Rubio A, Yekhlef L, Cancellieri C, Dusi S, Giannelli SG, Venco P, Mazzara PG, Cozzi A, Ferrari M, Garavaglia B, Taverna S, Tiranti V, Broccoli V, and Levi S
- Subjects
- Cell Death, Cells, Cultured, Humans, Mitochondria pathology, Pluripotent Stem Cells physiology, Reactive Oxygen Species metabolism, Coenzyme A metabolism, Neurons pathology, Pantothenate Kinase-Associated Neurodegeneration physiopathology, Phosphotransferases (Alcohol Group Acceptor) deficiency
- 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., (© 2016 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2016
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