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Mitochondrial dysfunction and calcium dysregulation in COQ8A-ataxia Purkinje neurons are rescued by CoQ10 treatment.
Manolaras, Ioannis; Del Bondio, Andrea; Griso, Olivier; Reutenauer, Laurence; Eisenmann, Aurélie; Habermann, Bianca H; Puccio, Hélène.
Afiliación
  • Manolaras I; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of translational medecine and neurogenetics, 67404 Illkirch, France.
  • Del Bondio A; Inserm, U1258, 67404 Illkirch, France.
  • Griso O; CNRS, UMR7104, 67404 Illkirch, France.
  • Reutenauer L; Université de Strasbourg, 67000 Strasbourg, France.
  • Eisenmann A; Institut Neuromyogène, Pathophysiology and genetics of the neuron and muscle, Inserm U1315, 69008 Lyon, France.
  • Habermann BH; CNRS, Université Claude Bernard Lyon I, UMR 5261, 69008 Lyon, France.
  • Puccio H; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of translational medecine and neurogenetics, 67404 Illkirch, France.
Brain ; 146(9): 3836-3850, 2023 09 01.
Article en En | MEDLINE | ID: mdl-36960552
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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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Ataxia Cerebelosa Límite: Animals Idioma: En Revista: Brain Año: 2023 Tipo del documento: Article País de afiliación: Francia

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Ataxia Cerebelosa Límite: Animals Idioma: En Revista: Brain Año: 2023 Tipo del documento: Article País de afiliación: Francia