IronSulferCluV1, Main, Exploration, bibRecord, 000248

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

Identifieur interne : 000248 ( Main/Exploration ); précédent : 000247

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

Auteurs : Suh Young Jeong [États-Unis] ; Penelope Hogarth [États-Unis] ; Andrew Placzek [États-Unis] ; Allison M. Gregory [États-Unis] ; Rachel Fox [États-Unis] ; Dolly Zhen [États-Unis] ; Jeffrey Hamada [États-Unis] ; Marianne Van Der Zwaag [Pays-Bas] ; Roald Lambrechts [Pays-Bas] ; Haihong Jin [États-Unis] ; Aaron Nilsen [États-Unis] ; Jared Cobb [États-Unis] ; Thao Pham [États-Unis] ; Nora Gray [États-Unis] ; Martina Ralle [États-Unis] ; Megan Duffy [États-Unis] ; Leila Schwanemann [États-Unis] ; Puneet Rai [États-Unis] ; Alison Freed [États-Unis] ; Katrina Wakeman [États-Unis] ; Randall L. Woltjer [États-Unis] ; Ody Cm Sibon [Pays-Bas] ; Susan J. Hayflick [États-Unis]

Source :

EMBO molecular medicine [ 1757-4684 ] ; 2019.

RBID : pubmed:31660701

Descripteurs français

KwdFr :
- Animaux (MeSH), Coenzyme A (métabolisme), Dopamine (métabolisme), Fer (métabolisme), Génotype (MeSH), Marqueurs biologiques (métabolisme), Neurodégénérescence associée à la pantothénate kinase (métabolisme), Neurodégénérescence associée à la pantothénate kinase (traitement médicamenteux), Pantéthéine (analogues et dérivés), Pantéthéine (pharmacologie), Pantéthéine (usage thérapeutique), Phosphotransferases (Alcohol Group Acceptor) (métabolisme), Souris (MeSH).
MESH :
- analogues et dérivés : Pantéthéine.
- métabolisme : Coenzyme A, Dopamine, Fer, Marqueurs biologiques, Neurodégénérescence associée à la pantothénate kinase, Phosphotransferases (Alcohol Group Acceptor).
- pharmacologie : Pantéthéine.
- traitement médicamenteux : Neurodégénérescence associée à la pantothénate kinase.
- usage thérapeutique : Pantéthéine.
- Animaux, Génotype, Souris.

English descriptors

KwdEn :
- Animals (MeSH), Biomarkers (metabolism), Coenzyme A (metabolism), Dopamine (metabolism), Genotype (MeSH), Iron (metabolism), Mice (MeSH), Pantetheine (analogs & derivatives), Pantetheine (pharmacology), Pantetheine (therapeutic use), Pantothenate Kinase-Associated Neurodegeneration (drug therapy), Pantothenate Kinase-Associated Neurodegeneration (metabolism), Phosphotransferases (Alcohol Group Acceptor) (metabolism).
MESH :
- chemical , analogs & derivatives : Pantetheine.
- chemical , metabolism : Biomarkers, Coenzyme A, Dopamine, Iron, Phosphotransferases (Alcohol Group Acceptor).
- chemical , pharmacology : Pantetheine.
- chemical , therapeutic use : Pantetheine.
- drug therapy : Pantothenate Kinase-Associated Neurodegeneration.
- metabolism : Pantothenate Kinase-Associated Neurodegeneration.
- Animals, Genotype, Mice.

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.

DOI: 10.15252/emmm.201910489
PubMed: 31660701
PubMed Central: PMC6895607

Affiliations:

Links toward previous steps (curation, corpus...)

to stream Main, to step Corpus: 000208
to stream Main, to step Curation: 000208

Le document en format XML

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<author><name sortKey="Cobb, Jared" sort="Cobb, Jared" uniqKey="Cobb J" first="Jared" last="Cobb">Jared Cobb</name>
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<author><name sortKey="Pham, Thao" sort="Pham, Thao" uniqKey="Pham T" first="Thao" last="Pham">Thao Pham</name>
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<author><name sortKey="Gray, Nora" sort="Gray, Nora" uniqKey="Gray N" first="Nora" last="Gray">Nora Gray</name>
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<author><name sortKey="Ralle, Martina" sort="Ralle, Martina" uniqKey="Ralle M" first="Martina" last="Ralle">Martina Ralle</name>
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<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
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<author><name sortKey="Duffy, Megan" sort="Duffy, Megan" uniqKey="Duffy M" first="Megan" last="Duffy">Megan Duffy</name>
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<author><name sortKey="Schwanemann, Leila" sort="Schwanemann, Leila" uniqKey="Schwanemann L" first="Leila" last="Schwanemann">Leila Schwanemann</name>
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<country xml:lang="fr">États-Unis</country>
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<author><name sortKey="Rai, Puneet" sort="Rai, Puneet" uniqKey="Rai P" first="Puneet" last="Rai">Puneet Rai</name>
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<author><name sortKey="Freed, Alison" sort="Freed, Alison" uniqKey="Freed A" first="Alison" last="Freed">Alison Freed</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
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<author><name sortKey="Wakeman, Katrina" sort="Wakeman, Katrina" uniqKey="Wakeman K" first="Katrina" last="Wakeman">Katrina Wakeman</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Woltjer, Randall L" sort="Woltjer, Randall L" uniqKey="Woltjer R" first="Randall L" last="Woltjer">Randall L. Woltjer</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Pathology, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
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<author><name sortKey="Sibon, Ody Cm" sort="Sibon, Ody Cm" uniqKey="Sibon O" first="Ody Cm" last="Sibon">Ody Cm Sibon</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Cell Biology, University Medical Center Groningen, Groningen, the Netherlands.</nlm:affiliation>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Cell Biology, University Medical Center Groningen, Groningen</wicri:regionArea>
<placeName><settlement type="city">Groningue</settlement>
<region nuts="2" type="province">Groningue (province)</region>
</placeName>
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<author><name sortKey="Hayflick, Susan J" sort="Hayflick, Susan J" uniqKey="Hayflick S" first="Susan J" last="Hayflick">Susan J. Hayflick</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
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<affiliation wicri:level="4"><nlm:affiliation>Department of Neurology, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:affiliation>Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">4'-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN.</title>
<author><name sortKey="Jeong, Suh Young" sort="Jeong, Suh Young" uniqKey="Jeong S" first="Suh Young" last="Jeong">Suh Young Jeong</name>
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<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Hogarth, Penelope" sort="Hogarth, Penelope" uniqKey="Hogarth P" first="Penelope" last="Hogarth">Penelope Hogarth</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
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<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
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<affiliation wicri:level="4"><nlm:affiliation>Department of Neurology, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Placzek, Andrew" sort="Placzek, Andrew" uniqKey="Placzek A" first="Andrew" last="Placzek">Andrew Placzek</name>
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<country xml:lang="fr">États-Unis</country>
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<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Gregory, Allison M" sort="Gregory, Allison M" uniqKey="Gregory A" first="Allison M" last="Gregory">Allison M. Gregory</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Fox, Rachel" sort="Fox, Rachel" uniqKey="Fox R" first="Rachel" last="Fox">Rachel Fox</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Zhen, Dolly" sort="Zhen, Dolly" uniqKey="Zhen D" first="Dolly" last="Zhen">Dolly Zhen</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Hamada, Jeffrey" sort="Hamada, Jeffrey" uniqKey="Hamada J" first="Jeffrey" last="Hamada">Jeffrey Hamada</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Van Der Zwaag, Marianne" sort="Van Der Zwaag, Marianne" uniqKey="Van Der Zwaag M" first="Marianne" last="Van Der Zwaag">Marianne Van Der Zwaag</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Cell Biology, University Medical Center Groningen, Groningen, the Netherlands.</nlm:affiliation>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Cell Biology, University Medical Center Groningen, Groningen</wicri:regionArea>
<placeName><settlement type="city">Groningue</settlement>
<region nuts="2" type="province">Groningue (province)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lambrechts, Roald" sort="Lambrechts, Roald" uniqKey="Lambrechts R" first="Roald" last="Lambrechts">Roald Lambrechts</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Cell Biology, University Medical Center Groningen, Groningen, the Netherlands.</nlm:affiliation>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Cell Biology, University Medical Center Groningen, Groningen</wicri:regionArea>
<placeName><settlement type="city">Groningue</settlement>
<region nuts="2" type="province">Groningue (province)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Jin, Haihong" sort="Jin, Haihong" uniqKey="Jin H" first="Haihong" last="Jin">Haihong Jin</name>
<affiliation wicri:level="4"><nlm:affiliation>Medicinal Chemistry Core, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Medicinal Chemistry Core, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Nilsen, Aaron" sort="Nilsen, Aaron" uniqKey="Nilsen A" first="Aaron" last="Nilsen">Aaron Nilsen</name>
<affiliation wicri:level="4"><nlm:affiliation>Medicinal Chemistry Core, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Medicinal Chemistry Core, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Cobb, Jared" sort="Cobb, Jared" uniqKey="Cobb J" first="Jared" last="Cobb">Jared Cobb</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Pathology, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Pham, Thao" sort="Pham, Thao" uniqKey="Pham T" first="Thao" last="Pham">Thao Pham</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Pathology, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Gray, Nora" sort="Gray, Nora" uniqKey="Gray N" first="Nora" last="Gray">Nora Gray</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Neurology, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Ralle, Martina" sort="Ralle, Martina" uniqKey="Ralle M" first="Martina" last="Ralle">Martina Ralle</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Duffy, Megan" sort="Duffy, Megan" uniqKey="Duffy M" first="Megan" last="Duffy">Megan Duffy</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Schwanemann, Leila" sort="Schwanemann, Leila" uniqKey="Schwanemann L" first="Leila" last="Schwanemann">Leila Schwanemann</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Rai, Puneet" sort="Rai, Puneet" uniqKey="Rai P" first="Puneet" last="Rai">Puneet Rai</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Freed, Alison" sort="Freed, Alison" uniqKey="Freed A" first="Alison" last="Freed">Alison Freed</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Wakeman, Katrina" sort="Wakeman, Katrina" uniqKey="Wakeman K" first="Katrina" last="Wakeman">Katrina Wakeman</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Woltjer, Randall L" sort="Woltjer, Randall L" uniqKey="Woltjer R" first="Randall L" last="Woltjer">Randall L. Woltjer</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Pathology, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
</author>
<author><name sortKey="Sibon, Ody Cm" sort="Sibon, Ody Cm" uniqKey="Sibon O" first="Ody Cm" last="Sibon">Ody Cm Sibon</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Cell Biology, University Medical Center Groningen, Groningen, the Netherlands.</nlm:affiliation>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Cell Biology, University Medical Center Groningen, Groningen</wicri:regionArea>
<placeName><settlement type="city">Groningue</settlement>
<region nuts="2" type="province">Groningue (province)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Hayflick, Susan J" sort="Hayflick, Susan J" uniqKey="Hayflick S" first="Susan J" last="Hayflick">Susan J. Hayflick</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:affiliation>Department of Neurology, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:affiliation>Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Oregon Health & Science University, Portland, OR</wicri:regionArea>
<placeName><region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
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<series><title level="j">EMBO molecular medicine</title>
<idno type="eISSN">1757-4684</idno>
<imprint><date when="2019" type="published">2019</date>
</imprint>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term>
<term>Biomarkers (metabolism)</term>
<term>Coenzyme A (metabolism)</term>
<term>Dopamine (metabolism)</term>
<term>Genotype (MeSH)</term>
<term>Iron (metabolism)</term>
<term>Mice (MeSH)</term>
<term>Pantetheine (analogs & derivatives)</term>
<term>Pantetheine (pharmacology)</term>
<term>Pantetheine (therapeutic use)</term>
<term>Pantothenate Kinase-Associated Neurodegeneration (drug therapy)</term>
<term>Pantothenate Kinase-Associated Neurodegeneration (metabolism)</term>
<term>Phosphotransferases (Alcohol Group Acceptor) (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term>
<term>Coenzyme A (métabolisme)</term>
<term>Dopamine (métabolisme)</term>
<term>Fer (métabolisme)</term>
<term>Génotype (MeSH)</term>
<term>Marqueurs biologiques (métabolisme)</term>
<term>Neurodégénérescence associée à la pantothénate kinase (métabolisme)</term>
<term>Neurodégénérescence associée à la pantothénate kinase (traitement médicamenteux)</term>
<term>Pantéthéine (analogues et dérivés)</term>
<term>Pantéthéine (pharmacologie)</term>
<term>Pantéthéine (usage thérapeutique)</term>
<term>Phosphotransferases (Alcohol Group Acceptor) (métabolisme)</term>
<term>Souris (MeSH)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Pantetheine</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Biomarkers</term>
<term>Coenzyme A</term>
<term>Dopamine</term>
<term>Iron</term>
<term>Phosphotransferases (Alcohol Group Acceptor)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Pantetheine</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Pantetheine</term>
</keywords>
<keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Pantéthéine</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Pantothenate Kinase-Associated Neurodegeneration</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Pantothenate Kinase-Associated Neurodegeneration</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Coenzyme A</term>
<term>Dopamine</term>
<term>Fer</term>
<term>Marqueurs biologiques</term>
<term>Neurodégénérescence associée à la pantothénate kinase</term>
<term>Phosphotransferases (Alcohol Group Acceptor)</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Pantéthéine</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Neurodégénérescence associée à la pantothénate kinase</term>
</keywords>
<keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Pantéthéine</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Genotype</term>
<term>Mice</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Génotype</term>
<term>Souris</term>
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<front><div type="abstract" xml:lang="en">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.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">31660701</PMID>
<DateCompleted><Year>2020</Year>
<Month>04</Month>
<Day>27</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>05</Month>
<Day>07</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1757-4684</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>11</Volume>
<Issue>12</Issue>
<PubDate><Year>2019</Year>
<Month>12</Month>
</PubDate>
</JournalIssue>
<Title>EMBO molecular medicine</Title>
<ISOAbbreviation>EMBO Mol Med</ISOAbbreviation>
</Journal>
<ArticleTitle>4'-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN.</ArticleTitle>
<Pagination><MedlinePgn>e10489</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.15252/emmm.201910489</ELocationID>
<Abstract><AbstractText>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.</AbstractText>
<CopyrightInformation>© 2019 The Authors. Published under the terms of the CC BY 4.0 license.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Jeong</LastName>
<ForeName>Suh Young</ForeName>
<Initials>SY</Initials>
<Identifier Source="ORCID">0000-0002-6376-7001</Identifier>
<AffiliationInfo><Affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Hogarth</LastName>
<ForeName>Penelope</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Neurology, Oregon Health & Science University, Portland, OR, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Placzek</LastName>
<ForeName>Andrew</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Medicinal Chemistry Core, Oregon Health & Science University, Portland, OR, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Gregory</LastName>
<ForeName>Allison M</ForeName>
<Initials>AM</Initials>
<AffiliationInfo><Affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Fox</LastName>
<ForeName>Rachel</ForeName>
<Initials>R</Initials>
<Identifier Source="ORCID">0000-0001-6265-2256</Identifier>
<AffiliationInfo><Affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Zhen</LastName>
<ForeName>Dolly</ForeName>
<Initials>D</Initials>
<AffiliationInfo><Affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Hamada</LastName>
<ForeName>Jeffrey</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>van der Zwaag</LastName>
<ForeName>Marianne</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Department of Cell Biology, University Medical Center Groningen, Groningen, the Netherlands.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lambrechts</LastName>
<ForeName>Roald</ForeName>
<Initials>R</Initials>
<AffiliationInfo><Affiliation>Department of Cell Biology, University Medical Center Groningen, Groningen, the Netherlands.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Jin</LastName>
<ForeName>Haihong</ForeName>
<Initials>H</Initials>
<AffiliationInfo><Affiliation>Medicinal Chemistry Core, Oregon Health & Science University, Portland, OR, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Nilsen</LastName>
<ForeName>Aaron</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Medicinal Chemistry Core, Oregon Health & Science University, Portland, OR, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Cobb</LastName>
<ForeName>Jared</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Department of Pathology, Oregon Health & Science University, Portland, OR, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Pham</LastName>
<ForeName>Thao</ForeName>
<Initials>T</Initials>
<AffiliationInfo><Affiliation>Department of Pathology, Oregon Health & Science University, Portland, OR, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Gray</LastName>
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<Initials>N</Initials>
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<name sortKey="Lambrechts, Roald" sort="Lambrechts, Roald" uniqKey="Lambrechts R" first="Roald" last="Lambrechts">Roald Lambrechts</name>
<name sortKey="Sibon, Ody Cm" sort="Sibon, Ody Cm" uniqKey="Sibon O" first="Ody Cm" last="Sibon">Ody Cm Sibon</name>
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{{Explor lien
   |wiki=    Bois
   |area=    IronSulferCluV1
   |flux=    Main
   |étape=   Exploration
   |type=    RBID
   |clé=     pubmed:31660701
   |texte=   4'-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN.
}}

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

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

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