Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation

Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited neurologic disorders in which iron accumulates in the basal ganglia resulting in progressive dystonia, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. The most prevalent...

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Autores: Álvarez Córdoba, Mónica, Fernández Khoury, Aida, Villanueva Paz, Marina, Gómez Navarro, Carmen, Villalón García, Irene, Suárez Rivero, Juan M., Povea Cabello, Suleva, Mata, Mario de la, Cotán, David, Talaverón Rey, Marta, Pérez Pulido, Antonio J., Salas, Joaquín J., Pérez Villegas, Eva Mª, Díaz Quintana, Antonio Jesús, Armengol, José A., Sánchez Alcázar, José A.
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2019
País:España
Institución:Universidad de Sevilla (US)
Repositorio:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/142242
Acceso en línea:https://hdl.handle.net/11441/142242
https://doi.org/10.1007/s12035-018-1333-0
Access Level:acceso abierto
Palabra clave:Coenzyme A
Induced neurons
Mitochondria
Pantothenate
Pantothenate kinase
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spelling Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of MutationÁlvarez Córdoba, MónicaFernández Khoury, AidaVillanueva Paz, MarinaGómez Navarro, CarmenVillalón García, IreneSuárez Rivero, Juan M.Povea Cabello, SulevaMata, Mario de laCotán, DavidTalaverón Rey, MartaPérez Pulido, Antonio J.Salas, Joaquín J.Pérez Villegas, Eva MªDíaz Quintana, Antonio JesúsArmengol, José A.Sánchez Alcázar, José A.Coenzyme AInduced neuronsMitochondriaPantothenatePantothenate kinaseNeurodegeneration with brain iron accumulation (NBIA) is a group of inherited neurologic disorders in which iron accumulates in the basal ganglia resulting in progressive dystonia, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. The most prevalent form of NBIA is pantothenate kinase-associated neurodegeneration (PKAN) associated with mutations in the gene of pantothenate kinase 2 (PANK2), which is essential for coenzyme A (CoA) synthesis. There is no cure for NBIA nor is there a standard course of treatment. In the current work, we describe that fibroblasts derived from patients harbouring PANK2 mutations can reproduce many of the cellular pathological alterations found in the disease, such as intracellular iron and lipofuscin accumulation, increased oxidative stress, and mitochondrial dysfunction. Furthermore, mutant fibroblasts showed a characteristic senescent morphology. Treatment with pantothenate, the PANK2 enzyme substrate, was able to correct all pathological alterations in responder mutant fibroblasts with residual PANK2 enzyme expression. However, pantothenate had no effect on mutant fibroblasts with truncated/incomplete protein expression. The positive effect of pantothenate in particular mutations was also confirmed in induced neurons obtained by direct reprograming of mutant fibroblasts. Our results suggest that pantothenate treatment can stabilize the expression levels of PANK2 in selected mutations. These results encourage us to propose our screening model as a quick and easy way to detect pantothenate-responder patients with PANK2 mutations. The existence of residual enzyme expression in some affected individuals raises the possibility of treatment using high dose of pantothenate.Instituto de Salud Carlos III FIS PI16/00786Junta de Andalucía CTS-5725, BIO-122Dirección General de Investigación Científica y Técnica BFU2015-64536-RSpringer NatureBioquímica Vegetal y Biología MolecularInstituto de Salud Carlos IIIEuropean Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)Junta de AndalucíaDirección General de Investigación Científica y Técnica (DGICYT). España2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/142242https://doi.org/10.1007/s12035-018-1333-0reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésMolecular Neurobiology, 56 (5), 3638-3656.FIS PI16/00786CTS-5725BIO-122BFU2015-64536-Rhttps://doi.org/10.1007/s12035-018-1333-0info:eu-repo/semantics/openAccessoai:idus.us.es:11441/1422422026-06-17T12:51:07Z
dc.title.none.fl_str_mv Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation
title Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation
spellingShingle Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation
Álvarez Córdoba, Mónica
Coenzyme A
Induced neurons
Mitochondria
Pantothenate
Pantothenate kinase
title_short Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation
title_full Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation
title_fullStr Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation
title_full_unstemmed Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation
title_sort Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation
dc.creator.none.fl_str_mv Álvarez Córdoba, Mónica
Fernández Khoury, Aida
Villanueva Paz, Marina
Gómez Navarro, Carmen
Villalón García, Irene
Suárez Rivero, Juan M.
Povea Cabello, Suleva
Mata, Mario de la
Cotán, David
Talaverón Rey, Marta
Pérez Pulido, Antonio J.
Salas, Joaquín J.
Pérez Villegas, Eva Mª
Díaz Quintana, Antonio Jesús
Armengol, José A.
Sánchez Alcázar, José A.
author Álvarez Córdoba, Mónica
author_facet Álvarez Córdoba, Mónica
Fernández Khoury, Aida
Villanueva Paz, Marina
Gómez Navarro, Carmen
Villalón García, Irene
Suárez Rivero, Juan M.
Povea Cabello, Suleva
Mata, Mario de la
Cotán, David
Talaverón Rey, Marta
Pérez Pulido, Antonio J.
Salas, Joaquín J.
Pérez Villegas, Eva Mª
Díaz Quintana, Antonio Jesús
Armengol, José A.
Sánchez Alcázar, José A.
author_role author
author2 Fernández Khoury, Aida
Villanueva Paz, Marina
Gómez Navarro, Carmen
Villalón García, Irene
Suárez Rivero, Juan M.
Povea Cabello, Suleva
Mata, Mario de la
Cotán, David
Talaverón Rey, Marta
Pérez Pulido, Antonio J.
Salas, Joaquín J.
Pérez Villegas, Eva Mª
Díaz Quintana, Antonio Jesús
Armengol, José A.
Sánchez Alcázar, José A.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Bioquímica Vegetal y Biología Molecular
Instituto de Salud Carlos III
European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
Junta de Andalucía
Dirección General de Investigación Científica y Técnica (DGICYT). España
dc.subject.none.fl_str_mv Coenzyme A
Induced neurons
Mitochondria
Pantothenate
Pantothenate kinase
topic Coenzyme A
Induced neurons
Mitochondria
Pantothenate
Pantothenate kinase
description Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited neurologic disorders in which iron accumulates in the basal ganglia resulting in progressive dystonia, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. The most prevalent form of NBIA is pantothenate kinase-associated neurodegeneration (PKAN) associated with mutations in the gene of pantothenate kinase 2 (PANK2), which is essential for coenzyme A (CoA) synthesis. There is no cure for NBIA nor is there a standard course of treatment. In the current work, we describe that fibroblasts derived from patients harbouring PANK2 mutations can reproduce many of the cellular pathological alterations found in the disease, such as intracellular iron and lipofuscin accumulation, increased oxidative stress, and mitochondrial dysfunction. Furthermore, mutant fibroblasts showed a characteristic senescent morphology. Treatment with pantothenate, the PANK2 enzyme substrate, was able to correct all pathological alterations in responder mutant fibroblasts with residual PANK2 enzyme expression. However, pantothenate had no effect on mutant fibroblasts with truncated/incomplete protein expression. The positive effect of pantothenate in particular mutations was also confirmed in induced neurons obtained by direct reprograming of mutant fibroblasts. Our results suggest that pantothenate treatment can stabilize the expression levels of PANK2 in selected mutations. These results encourage us to propose our screening model as a quick and easy way to detect pantothenate-responder patients with PANK2 mutations. The existence of residual enzyme expression in some affected individuals raises the possibility of treatment using high dose of pantothenate.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11441/142242
https://doi.org/10.1007/s12035-018-1333-0
url https://hdl.handle.net/11441/142242
https://doi.org/10.1007/s12035-018-1333-0
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Molecular Neurobiology, 56 (5), 3638-3656.
FIS PI16/00786
CTS-5725
BIO-122
BFU2015-64536-R
https://doi.org/10.1007/s12035-018-1333-0
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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