4 '-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN

Suh Young Jeong, Penelope Hogarth, Andrew Placzek, Allison M. Gregory, Rachel Fox, Dolly Zhen, Jeffrey Hamada, Marianne van der Zwaag, Roald Lambrechts, Haihong Jin, Aaron Nilsen, Jared S. Cobb, Thao Pham, Nora Gray, Martina Ralle, Megan Du, Leila Schwanemann, Puneet Rai, Alison Freed, Katrina WakemanRandall L. Woltjer, Ody C. M. Sibon, Susan J. Hayflick*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

49 Citaten (Scopus)
170 Downloads (Pure)


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.

Originele taal-2English
Aantal pagina's17
TijdschriftEMBO Molecular Medicine
StatusPublished - 29-okt.-2019

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