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EMBO Mol Med. 2016 Oct 4;8(10):1197-1211. doi: 10.15252/emmm.201606391. Print 2016 Oct.

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

Author information

1
Proteomics of Iron Metabolism Unit, Division of Neuroscience San Raffaele Scientific Institute, Milan, Italy.
2
Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
3
Neuroimmunology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
4
Molecular Neurogenetics Unit, Foundation IRCCS-Neurological Institute "Carlo Besta", Milan, Italy.
5
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.
6
Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy Institute of Neuroscience, National Research Council, Milan, Italy.
7
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.

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.

KEYWORDS:

PKAN ; Coenzyme A; hiPSC; iron; neurodegeneration

PMID:
27516453
PMCID:
PMC5048368
DOI:
10.15252/emmm.201606391
[Indexed for MEDLINE]
Free PMC Article

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