Open Access4′‐Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN
Author(s) -
Jeong Suh Young,
Hogarth Penelope,
Placzek Andrew,
Gregory Allison M,
Fox Rachel,
Zhen Dolly,
Hamada Jeffrey,
van der Zwaag Marianne,
Lambrechts Roald,
Jin Haihong,
Nilsen Aaron,
Cobb Jared,
Pham Thao,
Gray Nora,
Ralle Martina,
Duffy Megan,
Schwanemann Leila,
Rai Puneet,
Freed Alison,
Wakeman Katrina,
Woltjer Randall L,
Sibon Ody CM,
Hayflick Susan J
Publication year - 2019
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201910489
Subject(s) - dopamine , biochemistry , coenzyme a , chemistry , biology , endocrinology , enzyme , reductase
Pantothenate kinase‐associated neurodegeneration ( PKAN ) is an inborn error of CoA metabolism causing dystonia, parkinsonism, and brain iron accumulation. Lack of a good mammalian model has impeded studies of pathogenesis and development of rational therapeutics. We took a new approach to investigating an existing mouse mutant of Pank2 and found that isolating the disease‐vulnerable brain revealed regional perturbations in CoA metabolism, iron homeostasis, and dopamine metabolism and functional defects in complex I and pyruvate dehydrogenase. Feeding mice a CoA pathway intermediate, 4′‐phosphopantetheine, normalized levels of the CoA‐, iron‐, and dopamine‐related biomarkers as well as activities of mitochondrial enzymes. Human cell changes also were recovered by 4′‐phosphopantetheine. We can mechanistically link a defect in CoA metabolism to these secondary effects via the activation of mitochondrial acyl carrier protein, which is essential to oxidative phosphorylation, iron–sulfur cluster biogenesis, and mitochondrial fatty acid synthesis. We demonstrate the fidelity of our model in recapitulating features of the human disease. Moreover, we identify pharmacodynamic biomarkers, provide insights into disease pathogenesis, and offer evidence for 4′‐phosphopantetheine as a candidate therapeutic for PKAN .