Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations

Friedreich Ataxia (FA) is a rare neuro-cardiodegenerative disease caused by mutations in the frataxin (FXN) gene. The most prevalent mutation is a GAA expansion in the first intron of the gene causing decreased frataxin expression. Some patients present the GAA expansion in one allele and a missense...

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Autores: Medina Carbonero, Marta, Sanz Alcázar, Arabela, Britti, Elena, Delaspre, Fabien, Cabiscol Català, Elisa, Ros Salvador, Joaquim, Tamarit Sumalla, Jordi
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/73417
Acceso en línea:https://doi.org/10.1007/s00018-021-04100-5
http://hdl.handle.net/10459.1/73417
Access Level:acceso abierto
Palabra clave:Friedreich Ataxia
Iron–sulfur
Mitochondria
OXPHOS
Oxidative stress
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spelling Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterationsMedina Carbonero, MartaSanz Alcázar, ArabelaBritti, ElenaDelaspre, FabienCabiscol Català, ElisaRos Salvador, JoaquimTamarit Sumalla, JordiFriedreich AtaxiaIron–sulfurMitochondriaOXPHOSOxidative stressFriedreich Ataxia (FA) is a rare neuro-cardiodegenerative disease caused by mutations in the frataxin (FXN) gene. The most prevalent mutation is a GAA expansion in the first intron of the gene causing decreased frataxin expression. Some patients present the GAA expansion in one allele and a missense mutation in the other allele. One of these mutations, FXNI154F, was reported to result in decreased content of mature frataxin and increased presence of an insoluble intermediate proteoform in cellular models. By introducing this mutation into the murine Fxn gene (I151F, equivalent to human I154F) we have now analyzed the consequences of this pathological point mutation in vivo. We have observed that FXNI151F homozygous mice present low frataxin levels in all tissues, with no evidence of insoluble proteoforms. Moreover, they display neurological deficits resembling those observed in FA patients. Biochemical analysis of heart, cerebrum and cerebellum have revealed decreased content of components from OXPHOS complexes I and II, decreased aconitase activity, and alterations in antioxidant defenses. These mitochondrial alterations are more marked in the nervous system than in heart, precede the appearance of neurological symptoms, and are similar to those observed in other FA models. We conclude that the primary pathological mechanism underlying the I151F mutation is frataxin deficiency, like in patients carrying GAA expansions. Therefore, patients carrying the I154F mutation would benefit from frataxin replacement therapies. Furthermore, our results also show that the FXNI151F mouse is an excellent tool for analyzing tissue-specific consequences of frataxin deficiency and for testing new therapies.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. FXNI151F Het mice were generated thanks to the BeHeard Challenge hosted by the Rare Genomics Institute (CA, USA). This work has also been funded by grants from Association Française de l´Ataxie de Friedreich – AFAF (obtained by FD) and from Ministerio de Economía y Empresa (MINECO, Spain, SAF2017-83883-R) (obtained by JR and JT).SpringerBirkhäuser Verlag202220222022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.1007/s00018-021-04100-5http://hdl.handle.net/10459.1/73417http://hdl.handle.net/10459.1/73417reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)Inglésinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-83883-RReproducció del document publicat a: https://doi.org/10.1007/s00018-021-04100-5Cellular and Molecular Life Sciences, 2022, vol. 79, article number 74, p. 1-20cc-by (c)Authors, 2022info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/oai:recercat.cat:10459.1/734172026-05-29T05:05:01Z
dc.title.none.fl_str_mv Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations
title Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations
spellingShingle Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations
Medina Carbonero, Marta
Friedreich Ataxia
Iron–sulfur
Mitochondria
OXPHOS
Oxidative stress
title_short Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations
title_full Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations
title_fullStr Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations
title_full_unstemmed Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations
title_sort Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations
dc.creator.none.fl_str_mv Medina Carbonero, Marta
Sanz Alcázar, Arabela
Britti, Elena
Delaspre, Fabien
Cabiscol Català, Elisa
Ros Salvador, Joaquim
Tamarit Sumalla, Jordi
author Medina Carbonero, Marta
author_facet Medina Carbonero, Marta
Sanz Alcázar, Arabela
Britti, Elena
Delaspre, Fabien
Cabiscol Català, Elisa
Ros Salvador, Joaquim
Tamarit Sumalla, Jordi
author_role author
author2 Sanz Alcázar, Arabela
Britti, Elena
Delaspre, Fabien
Cabiscol Català, Elisa
Ros Salvador, Joaquim
Tamarit Sumalla, Jordi
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Friedreich Ataxia
Iron–sulfur
Mitochondria
OXPHOS
Oxidative stress
topic Friedreich Ataxia
Iron–sulfur
Mitochondria
OXPHOS
Oxidative stress
description Friedreich Ataxia (FA) is a rare neuro-cardiodegenerative disease caused by mutations in the frataxin (FXN) gene. The most prevalent mutation is a GAA expansion in the first intron of the gene causing decreased frataxin expression. Some patients present the GAA expansion in one allele and a missense mutation in the other allele. One of these mutations, FXNI154F, was reported to result in decreased content of mature frataxin and increased presence of an insoluble intermediate proteoform in cellular models. By introducing this mutation into the murine Fxn gene (I151F, equivalent to human I154F) we have now analyzed the consequences of this pathological point mutation in vivo. We have observed that FXNI151F homozygous mice present low frataxin levels in all tissues, with no evidence of insoluble proteoforms. Moreover, they display neurological deficits resembling those observed in FA patients. Biochemical analysis of heart, cerebrum and cerebellum have revealed decreased content of components from OXPHOS complexes I and II, decreased aconitase activity, and alterations in antioxidant defenses. These mitochondrial alterations are more marked in the nervous system than in heart, precede the appearance of neurological symptoms, and are similar to those observed in other FA models. We conclude that the primary pathological mechanism underlying the I151F mutation is frataxin deficiency, like in patients carrying GAA expansions. Therefore, patients carrying the I154F mutation would benefit from frataxin replacement therapies. Furthermore, our results also show that the FXNI151F mouse is an excellent tool for analyzing tissue-specific consequences of frataxin deficiency and for testing new therapies.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
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://doi.org/10.1007/s00018-021-04100-5
http://hdl.handle.net/10459.1/73417
http://hdl.handle.net/10459.1/73417
url https://doi.org/10.1007/s00018-021-04100-5
http://hdl.handle.net/10459.1/73417
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-83883-R
Reproducció del document publicat a: https://doi.org/10.1007/s00018-021-04100-5
Cellular and Molecular Life Sciences, 2022, vol. 79, article number 74, p. 1-20
dc.rights.none.fl_str_mv cc-by (c)Authors, 2022
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/4.0/
rights_invalid_str_mv cc-by (c)Authors, 2022
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Springer
Birkhäuser Verlag
publisher.none.fl_str_mv Springer
Birkhäuser Verlag
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
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