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 Cobb, Thao Pham, Nora Gray, Martina Ralle, Megan Duffy, Leila Schwanemann, Puneet Rai, Alison Freed, Katrina WakemanRandall L. Woltjer, Ody C.M. Sibon, Susan J. Hayflick

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere10489
JournalEMBO Molecular Medicine
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Pantothenate Kinase-Associated Neurodegeneration
Coenzyme A
Dopamine
Iron
Biomarkers
Acyl Carrier Protein
Electron Transport Complex I
Inborn Errors Metabolism
Dystonia
Oxidative Phosphorylation
Parkinsonian Disorders
Brain Diseases
Organelle Biogenesis
Pyruvic Acid
Homeostasis
Fatty Acids
4'-phosphopantetheine
Brain
Enzymes
Therapeutics

Keywords

  • 4′-phosphopantetheine
  • coenzyme A
  • NBIA
  • PANK2
  • PKAN

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

4′-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN. / 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 C.M.; Hayflick, Susan J.

In: EMBO Molecular Medicine, 01.01.2019.

Research output: Contribution to journalArticle

Jeong, SY, Hogarth, P, Placzek, A, Gregory, AM, Fox, R, Zhen, D, Hamada, J, van der Zwaag, M, Lambrechts, R, Jin, H, Nilsen, A, Cobb, J, Pham, T, Gray, N, Ralle, M, Duffy, M, Schwanemann, L, Rai, P, Freed, A, Wakeman, K, Woltjer, RL, Sibon, OCM & Hayflick, SJ 2019, '4′-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN', EMBO Molecular Medicine. https://doi.org/10.15252/emmm.201910489
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 C.M. ; Hayflick, Susan J. / 4′-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN. In: EMBO Molecular Medicine. 2019.
@article{0b0ccd9c8c9e4237b444ff2c38ef0acd,
title = "4′-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN",
abstract = "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.",
keywords = "4′-phosphopantetheine, coenzyme A, NBIA, PANK2, PKAN",
author = "Jeong, {Suh Young} and Penelope Hogarth and Andrew Placzek and Gregory, {Allison M.} and Rachel Fox and Dolly Zhen and Jeffrey Hamada and {van der Zwaag}, Marianne and Roald Lambrechts and Haihong Jin and Aaron Nilsen and Jared Cobb and Thao Pham and Nora Gray and Martina Ralle and Megan Duffy and Leila Schwanemann and Puneet Rai and Alison Freed and Katrina Wakeman and Woltjer, {Randall L.} and Sibon, {Ody C.M.} and Hayflick, {Susan J.}",
year = "2019",
month = "1",
day = "1",
doi = "10.15252/emmm.201910489",
language = "English (US)",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - 4′-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN

AU - Jeong, Suh Young

AU - Hogarth, Penelope

AU - Placzek, Andrew

AU - Gregory, Allison M.

AU - Fox, Rachel

AU - Zhen, Dolly

AU - Hamada, Jeffrey

AU - van der Zwaag, Marianne

AU - Lambrechts, Roald

AU - Jin, Haihong

AU - Nilsen, Aaron

AU - Cobb, Jared

AU - Pham, Thao

AU - Gray, Nora

AU - Ralle, Martina

AU - Duffy, Megan

AU - Schwanemann, Leila

AU - Rai, Puneet

AU - Freed, Alison

AU - Wakeman, Katrina

AU - Woltjer, Randall L.

AU - Sibon, Ody C.M.

AU - Hayflick, Susan J.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - 4′-phosphopantetheine

KW - coenzyme A

KW - NBIA

KW - PANK2

KW - PKAN

UR - http://www.scopus.com/inward/record.url?scp=85074703860&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85074703860&partnerID=8YFLogxK

U2 - 10.15252/emmm.201910489

DO - 10.15252/emmm.201910489

M3 - Article

C2 - 31660701

AN - SCOPUS:85074703860

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4676

M1 - e10489

ER -