Mitochondrial dysfunction and calcium dysregulation in COQ8A-ataxia Purkinje neurons are rescued by CoQ10 treatment

Manolaras et al. demonstrate that COQ8A-ataxia is primarily caused by mitochondrial dysfunction leading to calcium dysregulation in Purkinje neurons of the cerebellum. These abnormalities can be rescued in vitro by treatment with coenzyme Q10. 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 Q(10) 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 CoQ(10) treatment, suggesting that CoQ(10) could be a beneficial treatment for COQ8A-ataxia.