Mitochondrial dynamics and calcium homeostasis at the crossroad of the AFG3L2-associated pathway to cerebellar degeneration. From molecular hypothesis to preclinical treatment

Spinocerebellar ataxia type 28 (SCA28) is a neurodegenerative disease caused by mutations of the AFG3L2 gene. The encoded protein assembles into multimeric complexes (the m-AAA proteases), which exert protein quality control in the inner mitochondrial membrane and participate to the regulation of mitochondrial morphology. The Afg3l2 haploinsufficient mouse recapitulates the symptoms of SCA28 patients, presenting a progressive decline in motor skills caused by dark degeneration of Purkinje cells (PC-DCD) of mitochondrial origin. Here, we define the pathogenetic mechanism of SCA28 and provide the first evidence of a pre-clinical treatment of this disease. We demonstrated in cultured PCs that an inefficient buffering of stimulus-evoked Ca2+ peaks by Afg3l2-deficient mitochondria provokes an increase in cytoplasmic Ca2+ concentration, thus triggering PC-DCD. Proving this mechanism, we completely recover the ataxic phenotype of SCA28 mice by genetically reducing the metabotropic glutamate receptors mGluR1, and thus decreased Ca2+ influx in PCs. The same result has been successfully replicated by administration of an off-label therapy favoring the synaptic glutamate clearance. This treatment is effective when applied at both presymptomatic and after the ataxia onset in the preclinical model, thus representing a safe and immediately accessible therapy for presymptomatic carriers of AFG3L2 mutations and also SCA28 patients with overt symptoms.