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dc.contributor.authorRodríguez-Pascau, Laura
dc.contributor.authorBritti, Elena
dc.contributor.authorCalap Quintana, Pablo
dc.contributor.authorNa Dong, Yi
dc.contributor.authorVergara, Cristina
dc.contributor.authorDelaspre, Fabien
dc.contributor.authorMedina Carbonero, Marta
dc.contributor.authorTamarit Sumalla, Jordi
dc.contributor.authorPallardó, Federico V.
dc.contributor.authorGonzalez Cabo, Pilar
dc.contributor.authorRos, Joaquim
dc.contributor.authorLynch, David R.
dc.contributor.authorMartinell, Marc
dc.contributor.authorPizcueta, Pilar
dc.date.accessioned2021-10-20T07:10:02Z
dc.date.available2021-10-20T07:10:02Z
dc.date.issued2021
dc.identifier.issn0969-9961
dc.identifier.urihttp://hdl.handle.net/10459.1/72112
dc.description.abstractFriedreich 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 clus-ters (ISC), defective energy production, calcium dyshomeostasis, and impaired mitochondrial biogenesis, leading to mitochondrial dysfunction. The peroxisome proliferator-activated receptor gamma (PPARγ) 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 PPARγ/PPARγ coactivator 1 alpha (PGC-1α) pathway is dysregulated when there is frataxin deficiency, thus contributing to FRDA pathogenesis and supporting the PPARγ pathway as a potential therapeutic target. Here we assess whether MIN-102 (INN: leriglitazone), a novel brain penetrant and orally bioavailable PPARγ agonist with an improved profile for central nervous system (CNS) diseases, rescues phenotypic features in cellular and an-imal models of FRDA. In frataxin-deficient dorsal root ganglia (DRG) neurons, leriglitazone increased frataxin protein levels, reduced neurite degeneration and α-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+/Ca2+exchanger (NCLX), resulting in an improvement of mitochon-drial 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 PPARγ in mitochondrial biogenesis, leriglitazone significantly increased markers of mitochondrial biogenesis in FRDA patient cells. Overall, these results suggest that targeting the PPARγ pathway by leriglitazone may provide an efficacious therapy for FRDA increasing the mitochondrial function and biogenesis that could increase fra-taxin levels in compromised frataxin-deficient DRG neurons. Alternately, leriglitazone improved the energy metabolism by increasing the fatty acid β-oxidation in frataxin-deficient cardiomyocytes without elevation of frataxin levels. This could be linked to a lack of significant mitochondrial biogenesis and cardiac hypertrophy.ca_ES
dc.description.sponsorshipThis work was supported by Retos-Colaboraci ́on 2017 (RTC-2017- 5867-1), ENISA Jovenes Emprendedores 2012, Torres Quevedo 2017 (PTQ-17-09233) and Region Wallonne (SPW-EER/DRDT/DPjR/DEMO/ ML/D ́ef-7939).ca_ES
dc.language.isoengca_ES
dc.publisherElsevierca_ES
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.1016/j.nbd.2020.105162ca_ES
dc.relation.ispartofNeurobiology of Disease, 2021, vol. 148, 105162ca_ES
dc.rightscc-by-nc-nd (c) Rodríguez et al., 2021ca_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectFriedreich Ataxiaca_ES
dc.subjectFrataxinca_ES
dc.subjectNeurodegenerationca_ES
dc.subjectMitochondrial functionca_ES
dc.subjectDorsal root ganglia neuronsca_ES
dc.subjectCardiomyocytesca_ES
dc.titlePPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxiaca_ES
dc.typeinfo:eu-repo/semantics/articleca_ES
dc.identifier.idgrec031699
dc.type.versioninfo:eu-repo/semantics/publishedVersionca_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessca_ES
dc.identifier.doihttps://doi.org/10.1016/j.nbd.2020.105162


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cc-by-nc-nd (c) Rodríguez et al., 2021
Except where otherwise noted, this item's license is described as cc-by-nc-nd (c) Rodríguez et al., 2021