Mitochondrial dysfunction and calcium dysregulation in COQ8A-Ataxia Purkinje neurons are rescued by CoQ 10 treatment
In: ISSN: 0006-8950, 2023
Online
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Zugriff:
COQ8A-Ataxia is a rare form of neurodegenerative disorder due to mutations in the COQ8A gene. The encoded mitochondrial protein is involved in the regulation of Coenzyme Q10 biosynthesis. Previous studies on the constitutive Coq8a-/-mice indicated specific alterations of cerebellar Purkinje neurons involving altered electrophysiological function and dark cell degeneration. In the present manuscript, we extend our understanding of the contribution of Purkinje neuron dysfunction to the pathology. By generating a Purkinje specific conditional COQ8A knockout, we demonstrate that loss of COQ8A in Purkinje neurons is the main cause of cerebellar ataxia. Furthermore, through in vivo and in vitro approaches, we show that COQ8A-depleted Purkinje neurons have abnormal dendritic arborizations, altered mitochondria function and intracellular calcium dysregulation. Furthermore, we demonstrate that oxidative phosphorylation, in particular Complex IV, is primarily altered at presymptomatic stages of the disease. Finally, the morphology of primary Purkinje neurons as well as the mitochondrial dysfunction and calcium dysregulation could be rescued by CoQ10 treatment, suggesting that CoQ10 could be a beneficial treatment for COQ8A-Ataxia.
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Mitochondrial dysfunction and calcium dysregulation in COQ8A-Ataxia Purkinje neurons are rescued by CoQ 10 treatment
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Autor/in / Beteiligte Person: | Manolaras, Ioannis ; del Bondio, Andrea ; Griso, Olivier ; Reutenauer, Laurence ; Eisenmann, Aurélie ; Habermann, Bianca ; Puccio, Hélène ; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) ; Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) ; Institut NeuroMyoGène - Appui à la recherche (INMG-AR) ; Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) ; Institut de Biologie du Développement de Marseille (IBDM) ; Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS) ; ANR-15-RAR3-0011,PREPARE,Preparing for therapies in autosomal recessive ataxias(2015) ; ANR-10-LABX-0030,INRT,Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine(2010) ; ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010) |
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Zeitschrift: | ISSN: 0006-8950, 2023 |
Veröffentlichung: | HAL CCSD ; Oxford University Press (OUP), 2023 |
Medientyp: | academicJournal |
DOI: | 10.1093/brain/awad099 |
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