PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia.

Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy, and increased incidence in diabetes. The underlying pathophysiological mechanism of FRDA, driven by a significantly decrease...

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Autores: Rodriguez-Pascau, Laura, Britti, Elena, Calap-Quintana, Pablo, Dong, Yi Na, Vergara, Cristina, Delaspre, Fabien, Medina, Marta, Tamarit, Jordi, Pallardo, Federico V, Gonzalez-Cabo, Pilar, Ros, Joaquim, Lynch, David R, Martinell, Marc, Pizcueta, Pilar
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:INCLIVA
Repositorio:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
OAI Identifier:oai:incliva.fundanetsuite.com:p15096
Acceso en línea:https://incliva.portalinvestigacion.com/publicaciones/15096
Access Level:acceso abierto
Palabra clave:Cardiomyocytes
Dorsal root ganglia neurons
FRDA fibroblasts
Frataxin
Friedreich Ataxia
Leriglitazone
Mitochondrial function
Neurodegeneration
PPAR? agonist
YG8sR
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network_acronym_str ES
network_name_str España
repository_id_str
spelling PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia.Rodriguez-Pascau, LauraBritti, ElenaCalap-Quintana, PabloDong, Yi NaVergara, CristinaDelaspre, FabienMedina, MartaTamarit, JordiPallardo, Federico VGonzalez-Cabo, PilarRos, JoaquimLynch, David RMartinell, MarcPizcueta, PilarCardiomyocytesDorsal root ganglia neuronsFRDA fibroblastsFrataxinFriedreich AtaxiaLeriglitazoneMitochondrial functionNeurodegenerationPPAR? agonistYG8sRFriedreich ataxia (FRDA), the most common autosomal recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy, and increased incidence in diabetes. The underlying pathophysiological mechanism of FRDA, driven by a significantly decreased expression of frataxin (FXN), involves increased oxidative stress, reduced activity of enzymes containing iron-sulfur clusters (ISC), defective energy production, calcium dyshomeostasis, and impaired mitochondrial biogenesis, leading to mitochondrial dysfunction. The peroxisome proliferator-activated receptor gamma (PPAR?) is a ligand-activated transcriptional factor playing a key role in mitochondrial function and biogenesis, fatty acid storage, energy metabolism, and antioxidant defence. It has been previously shown that the PPAR?/PPAR? coactivator 1 alpha (PGC-1a) pathway is dysregulated when there is frataxin deficiency, thus contributing to FRDA pathogenesis and supporting the PPAR? pathway as a potential therapeutic target. Here we assess whether MIN-102 (INN: leriglitazone), a novel brain penetrant and orally bioavailable PPAR? agonist with an improved profile for central nervous system (CNS) diseases, rescues phenotypic features in cellular and animal models of FRDA. In frataxin-deficient dorsal root ganglia (DRG) neurons, leriglitazone increased frataxin protein levels, reduced neurite degeneration and a-fodrin cleavage mediated by calpain and caspase 3, and increased survival. Leriglitazone also restored mitochondrial membrane potential and partially reversed decreased levels of mitochondrial Na(+)/Ca(2+) exchanger (NCLX), resulting in an improvement of mitochondrial functions and calcium homeostasis. In frataxin-deficient primary neonatal cardiomyocytes, leriglitazone prevented lipid droplet accumulation without increases in frataxin levels. Furthermore, leriglitazone improved motor function deficit in YG8sR mice, a FRDA mouse model. In agreement with the role of PPAR? in mitochondrial biogenesis, leriglitazone significantly increased markers of mitochondrial biogenesis in FRDA patient cells. Overall, these results suggest that targeting the PPAR? pathway by leriglitazone may provide an efficacious therapy for FRDA increasing the mitochondrial function and biogenesis that could increase frataxin levels in compromised frataxin-deficient DRG neurons. Alternately, leriglitazone improved the energy metabolism by increasing the fatty acid ß-oxidation in frataxin-deficient cardiomyocytes without elevation of frataxin levels. This could be linked to a lack of significant mitochondrial biogenesis and cardiac hypertrophy. The results reinforced the different tissue requirement in FRDA and the pleiotropic effects of leriglitazone that could be a promising therapy for FRDA.ACADEMIC PRESS INC ELSEVIER SCIENCE2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://incliva.portalinvestigacion.com/publicaciones/15096NEUROBIOLOGY OF DISEASEISSN: 09699961ISSNe: 1095953Xreponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVAinstname:INCLIVAInglésinfo:eu-repo/semantics/openAccessoai:incliva.fundanetsuite.com:p150962026-06-07T16:35:31Z
dc.title.none.fl_str_mv PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia.
title PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia.
spellingShingle PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia.
Rodriguez-Pascau, Laura
Cardiomyocytes
Dorsal root ganglia neurons
FRDA fibroblasts
Frataxin
Friedreich Ataxia
Leriglitazone
Mitochondrial function
Neurodegeneration
PPAR? agonist
YG8sR
title_short PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia.
title_full PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia.
title_fullStr PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia.
title_full_unstemmed PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia.
title_sort PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia.
dc.creator.none.fl_str_mv Rodriguez-Pascau, Laura
Britti, Elena
Calap-Quintana, Pablo
Dong, Yi Na
Vergara, Cristina
Delaspre, Fabien
Medina, Marta
Tamarit, Jordi
Pallardo, Federico V
Gonzalez-Cabo, Pilar
Ros, Joaquim
Lynch, David R
Martinell, Marc
Pizcueta, Pilar
author Rodriguez-Pascau, Laura
author_facet Rodriguez-Pascau, Laura
Britti, Elena
Calap-Quintana, Pablo
Dong, Yi Na
Vergara, Cristina
Delaspre, Fabien
Medina, Marta
Tamarit, Jordi
Pallardo, Federico V
Gonzalez-Cabo, Pilar
Ros, Joaquim
Lynch, David R
Martinell, Marc
Pizcueta, Pilar
author_role author
author2 Britti, Elena
Calap-Quintana, Pablo
Dong, Yi Na
Vergara, Cristina
Delaspre, Fabien
Medina, Marta
Tamarit, Jordi
Pallardo, Federico V
Gonzalez-Cabo, Pilar
Ros, Joaquim
Lynch, David R
Martinell, Marc
Pizcueta, Pilar
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cardiomyocytes
Dorsal root ganglia neurons
FRDA fibroblasts
Frataxin
Friedreich Ataxia
Leriglitazone
Mitochondrial function
Neurodegeneration
PPAR? agonist
YG8sR
topic Cardiomyocytes
Dorsal root ganglia neurons
FRDA fibroblasts
Frataxin
Friedreich Ataxia
Leriglitazone
Mitochondrial function
Neurodegeneration
PPAR? agonist
YG8sR
description Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy, and increased incidence in diabetes. The underlying pathophysiological mechanism of FRDA, driven by a significantly decreased expression of frataxin (FXN), involves increased oxidative stress, reduced activity of enzymes containing iron-sulfur clusters (ISC), defective energy production, calcium dyshomeostasis, and impaired mitochondrial biogenesis, leading to mitochondrial dysfunction. The peroxisome proliferator-activated receptor gamma (PPAR?) is a ligand-activated transcriptional factor playing a key role in mitochondrial function and biogenesis, fatty acid storage, energy metabolism, and antioxidant defence. It has been previously shown that the PPAR?/PPAR? coactivator 1 alpha (PGC-1a) pathway is dysregulated when there is frataxin deficiency, thus contributing to FRDA pathogenesis and supporting the PPAR? pathway as a potential therapeutic target. Here we assess whether MIN-102 (INN: leriglitazone), a novel brain penetrant and orally bioavailable PPAR? agonist with an improved profile for central nervous system (CNS) diseases, rescues phenotypic features in cellular and animal models of FRDA. In frataxin-deficient dorsal root ganglia (DRG) neurons, leriglitazone increased frataxin protein levels, reduced neurite degeneration and a-fodrin cleavage mediated by calpain and caspase 3, and increased survival. Leriglitazone also restored mitochondrial membrane potential and partially reversed decreased levels of mitochondrial Na(+)/Ca(2+) exchanger (NCLX), resulting in an improvement of mitochondrial functions and calcium homeostasis. In frataxin-deficient primary neonatal cardiomyocytes, leriglitazone prevented lipid droplet accumulation without increases in frataxin levels. Furthermore, leriglitazone improved motor function deficit in YG8sR mice, a FRDA mouse model. In agreement with the role of PPAR? in mitochondrial biogenesis, leriglitazone significantly increased markers of mitochondrial biogenesis in FRDA patient cells. Overall, these results suggest that targeting the PPAR? pathway by leriglitazone may provide an efficacious therapy for FRDA increasing the mitochondrial function and biogenesis that could increase frataxin levels in compromised frataxin-deficient DRG neurons. Alternately, leriglitazone improved the energy metabolism by increasing the fatty acid ß-oxidation in frataxin-deficient cardiomyocytes without elevation of frataxin levels. This could be linked to a lack of significant mitochondrial biogenesis and cardiac hypertrophy. The results reinforced the different tissue requirement in FRDA and the pleiotropic effects of leriglitazone that could be a promising therapy for FRDA.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://incliva.portalinvestigacion.com/publicaciones/15096
url https://incliva.portalinvestigacion.com/publicaciones/15096
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv ACADEMIC PRESS INC ELSEVIER SCIENCE
publisher.none.fl_str_mv ACADEMIC PRESS INC ELSEVIER SCIENCE
dc.source.none.fl_str_mv NEUROBIOLOGY OF DISEASE
ISSN: 09699961
ISSNe: 1095953X
reponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
instname:INCLIVA
instname_str INCLIVA
reponame_str r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
collection r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
repository.name.fl_str_mv
repository.mail.fl_str_mv
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