Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from the Harlequin Mouse

By means of a proteomic approach, we assessed the pathways involved in cerebellar neurodegeneration in a mouse model (Harlequin, Hq) of mitochondrial disorder. A differential proteomic profile study (iTRAQ) was performed in cerebellum homogenates of male Hq and wild-type (WT) mice 8 weeks after the...

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Autores: Fernández de la Torre, Miguel, Fiuza-Luces, Carmen, Laine-Menéndez, Sara, Delmiro, Aitor, Arenas, Joaquín, Martín, Miguel Ángel, Lucia, Alejandro, Morán, María
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/330412
Acesso em linha:http://hdl.handle.net/10261/330412
Access Level:acceso abierto
Palavra-chave:Mitochondrial diseases
OXPHOS disorders
Complex I
Harlequin mouse
Ataxia
Long-term depression
Glutamate
GABA
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spelling Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from the Harlequin MouseFernández de la Torre, MiguelFiuza-Luces, CarmenLaine-Menéndez, SaraDelmiro, AitorArenas, JoaquínMartín, Miguel ÁngelLucia, AlejandroMorán, MaríaMitochondrial diseasesOXPHOS disordersComplex IHarlequin mouseAtaxiaLong-term depressionGlutamateGABABy means of a proteomic approach, we assessed the pathways involved in cerebellar neurodegeneration in a mouse model (Harlequin, Hq) of mitochondrial disorder. A differential proteomic profile study (iTRAQ) was performed in cerebellum homogenates of male Hq and wild-type (WT) mice 8 weeks after the onset of clear symptoms of ataxia in the Hq mice (aged 5.2 ± 0.2 and 5.3 ± 0.1 months for WT and Hq, respectively), followed by a biochemical validation of the most relevant changes. Additional groups of 2-, 3- and 6-month-old WT and Hq mice were analyzed to assess the disease progression on the proteins altered in the proteomic study. The proteomic analysis showed that beyond the expected deregulation of oxidative phosphorylation, the cerebellum of Hq mice showed a marked astroglial activation together with alterations in Ca2+ homeostasis and neurotransmission, with an up- and downregulation of GABAergic and glutamatergic neurotransmission, respectively, and the downregulation of cerebellar “long-term depression”, a synaptic plasticity phenomenon that is a major player in the error-driven learning that occurs in the cerebellar cortex. Our study provides novel insights into the mechanisms associated with cerebellar degeneration in the Hq mouse model, including a complex deregulation of neuroinflammation, oxidative phosphorylation and glutamate, GABA and amino acids’ metabolism.This study was funded by the Spanish Instituto de Salud Carlos III (ISCIII) through the projects PI17/00093 and PI20/00147, and co-funded by the European Union. Research by C.F.-L. is funded by a Miguel Servet postdoctoral contract granted by Instituto de Salud Carlos III (CP18/00034).Peer reviewedMultidisciplinary Digital Publishing InstituteInstituto de Salud Carlos IIIEuropean CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2023202320232023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/330412reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.3390/ijms241310973Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3304122026-05-22T06:33:51Z
dc.title.none.fl_str_mv Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from the Harlequin Mouse
title Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from the Harlequin Mouse
spellingShingle Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from the Harlequin Mouse
Fernández de la Torre, Miguel
Mitochondrial diseases
OXPHOS disorders
Complex I
Harlequin mouse
Ataxia
Long-term depression
Glutamate
GABA
title_short Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from the Harlequin Mouse
title_full Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from the Harlequin Mouse
title_fullStr Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from the Harlequin Mouse
title_full_unstemmed Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from the Harlequin Mouse
title_sort Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from the Harlequin Mouse
dc.creator.none.fl_str_mv Fernández de la Torre, Miguel
Fiuza-Luces, Carmen
Laine-Menéndez, Sara
Delmiro, Aitor
Arenas, Joaquín
Martín, Miguel Ángel
Lucia, Alejandro
Morán, María
author Fernández de la Torre, Miguel
author_facet Fernández de la Torre, Miguel
Fiuza-Luces, Carmen
Laine-Menéndez, Sara
Delmiro, Aitor
Arenas, Joaquín
Martín, Miguel Ángel
Lucia, Alejandro
Morán, María
author_role author
author2 Fiuza-Luces, Carmen
Laine-Menéndez, Sara
Delmiro, Aitor
Arenas, Joaquín
Martín, Miguel Ángel
Lucia, Alejandro
Morán, María
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Mitochondrial diseases
OXPHOS disorders
Complex I
Harlequin mouse
Ataxia
Long-term depression
Glutamate
GABA
topic Mitochondrial diseases
OXPHOS disorders
Complex I
Harlequin mouse
Ataxia
Long-term depression
Glutamate
GABA
description By means of a proteomic approach, we assessed the pathways involved in cerebellar neurodegeneration in a mouse model (Harlequin, Hq) of mitochondrial disorder. A differential proteomic profile study (iTRAQ) was performed in cerebellum homogenates of male Hq and wild-type (WT) mice 8 weeks after the onset of clear symptoms of ataxia in the Hq mice (aged 5.2 ± 0.2 and 5.3 ± 0.1 months for WT and Hq, respectively), followed by a biochemical validation of the most relevant changes. Additional groups of 2-, 3- and 6-month-old WT and Hq mice were analyzed to assess the disease progression on the proteins altered in the proteomic study. The proteomic analysis showed that beyond the expected deregulation of oxidative phosphorylation, the cerebellum of Hq mice showed a marked astroglial activation together with alterations in Ca2+ homeostasis and neurotransmission, with an up- and downregulation of GABAergic and glutamatergic neurotransmission, respectively, and the downregulation of cerebellar “long-term depression”, a synaptic plasticity phenomenon that is a major player in the error-driven learning that occurs in the cerebellar cortex. Our study provides novel insights into the mechanisms associated with cerebellar degeneration in the Hq mouse model, including a complex deregulation of neuroinflammation, oxidative phosphorylation and glutamate, GABA and amino acids’ metabolism.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/330412
url http://hdl.handle.net/10261/330412
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.3390/ijms241310973
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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