Coenzyme A corrects pathological defects in human neurons of PANK2-associated neurodegeneration

Daniel Ignacio Orellana Riquelme, Paolo Santambrogio, Alicia Rubio, Latefa Yekhlef, Cinzia Cancellieri, Sabrina Dusi, Serena Gea Giannelli, Paola Venco, Pietro G. Mazzara, Anna Cozzi, Maurizio Ferrari, Barbara Garavaglia, Stefano Taverna, Valeria Tiranti, Vania Broccoli, Sonia Levi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1197-1211
Number of pages15
JournalEMBO Molecular Medicine
Volume8
Issue number10
DOIs
Publication statusPublished - Oct 1 2016

Keywords

  • Coenzyme A
  • hiPSC
  • iron
  • neurodegeneration
  • PKAN

ASJC Scopus subject areas

  • Molecular Medicine

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