IL DIFETTO OSSIDATIVO E LE ALTERAZIONI DEL DNA MITOCONDRIALE IN TOPI TRANSGENICI MODELLO ANIMALE DELLA ATASSIA SPINOCEREBELLARE DI TIPO 1

Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of cerebellar degenerative disorders, characterized by progressive gait unsteadiness, hand incoordination and dysarthria. The mutational mechanism in spinocerebellar ataxia type1 (SCA1), a dominantly inherited form of SCA, consists of an expanded trinucleotide CAG repeat that encodes a polyglutamine tract in ataxin1. Mutant SCA1 transgenic mice present pathological cerebellar signs with concomitant progressive Purkinje neuron atrophy and relatively little cell loss, at least in the early stage of life; this evidence suggests that the SCA1 phenotype is not the result of cell death per se, but a possible effect of cellular dysfunction that occurs before neuronal demise. In the present study we correlated the earliest histopathological changes in both homozygous and heterozygous transgenic SCA1 mice, 2 and 6 months old, to the mitochondrial oxidative metabolism in cerebellar cells. Our results showed selective Cytochrome c Oxidase (COX) deficiency in Purkinje cells (PC). Analysis on COX-competent and -deficient PC, isolated by laser-microdissector, demonstrated that the observed oxidative dysfunction is related to mitochondrial DNA (mtDNA) depletion. In conclusion, we provide evidence of a selective oxidative metabolism defect in neuronal PC expressing mutant ataxin. This defect could represent one of the earliest pathogenetic step of the Purkinje cells’ suffering in SCA1 disease.