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

Autor: Jeong SY; Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA., Hogarth P; Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.; Department of Neurology, Oregon Health & Science University, Portland, OR, USA., Placzek A; Medicinal Chemistry Core, Oregon Health & Science University, Portland, OR, USA., Gregory AM; Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA., Fox R; Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA., Zhen D; Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA., Hamada J; Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA., van der Zwaag M; Department of Cell Biology, University Medical Center Groningen, Groningen, the Netherlands., Lambrechts R; Department of Cell Biology, University Medical Center Groningen, Groningen, the Netherlands., Jin H; Medicinal Chemistry Core, Oregon Health & Science University, Portland, OR, USA., Nilsen A; Medicinal Chemistry Core, Oregon Health & Science University, Portland, OR, USA., Cobb J; Department of Pathology, Oregon Health & Science University, Portland, OR, USA., Pham T; Department of Pathology, Oregon Health & Science University, Portland, OR, USA., Gray N; Department of Neurology, Oregon Health & Science University, Portland, OR, USA., Ralle M; Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA., Duffy M; Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA., Schwanemann L; Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA., Rai P; Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA., Freed A; Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA., Wakeman K; Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA., Woltjer RL; Department of Pathology, Oregon Health & Science University, Portland, OR, USA., Sibon OC; Department of Cell Biology, University Medical Center Groningen, Groningen, the Netherlands., Hayflick SJ; Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.; Department of Neurology, Oregon Health & Science University, Portland, OR, USA.; Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2019 Dec; Vol. 11 (12), pp. e10489. Date of Electronic Publication: 2019 Oct 29.
DOI: 10.15252/emmm.201910489
Abstrakt: 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.
(© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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