Purkinje cell COX deficiency and mtDNA depletion in an animal model of spinocerebellar ataxia type 1. Issue 9 (24th July 2018)

• Record Type: Journal Article
• Authors: Ripolone, Michela; Lucchini, Valeria; Ronchi, Dario; Fagiolari, Gigliola; Bordoni, Andreina; Fortunato, Francesco; Mondello, Stefania; Bonato, Sara; Meregalli, Mirella; Torrente, Yvan; Corti, Stefania; Comi, Giacomo P.; Moggio, Maurizio; Sciacco, Monica
• Is Part Of: Journal of neuroscience research. Volume 96:Issue 9(2018)
• Page Start: 1576
• Page End: 1585
• Publication Date: 2018-07-24
• Subjects: laser microdissector -- mitochondria -- mitochondrial DNA depletion -- oxidative damage -- Purkinje cell -- spinocerebellar ataxia type 1 -- transgenic mice; Neurobiology -- Periodicals; 612
• DOI: 10.1002/jnr.24263
• Languages: English
• ISSNs: 0360-4012

Abstract

Abstract: Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of cerebellar degenerative disorders, characterized by progressive gait unsteadiness, hand incoordination, and dysarthria. Ataxia type 1 (SCA1) is caused by the expansion of a CAG trinucleotide repeat in the SCA1 gene resulting in the atypical extension of a polyglutamine (polyQ) tract within the ataxin‐1 protein. Our main objective was to investigate the mitochondrial oxidative metabolism in the cerebellum of transgenic SCA1 mice. SCA1 transgenic mice develop clinical features in the early life stages (around 5 weeks of age) presenting pathological cerebellar signs with concomitant progressive Purkinje neuron atrophy and relatively little cell loss; 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. We studied the mitochondrial oxidative metabolism in cerebellar cells from both homozygous and heterozygous transgenic SCA1 mice, aged 2 and 6 months. Histochemical examination showed a cytochrome‐c‐oxidase (COX) deficiency in the Purkinje cells (PCs) of both heterozygous and homozygous mice, the oxidative defect being more prominent in older mice, in which the percentage of COX‐deficient PC was up to 30%. Using a laser‐microdissector, we evaluated the mitochondrial DNA (mtDNA) content on selectively isolated COX‐competent and COX‐deficient PC by quantitative Polymerase Chain Reaction and we found mtDNA depletion in those with oxidative dysfunction. In conclusion, the selective oxidative metabolism defect observed in neuronal PC expressing mutant ataxin occurs as early as 8 weeks of age thus representing an early step in the PC degeneration process in SCA1 disease. Abstract : This work uses an animal model to try to understand the pathogenesis of a progressive human disease (Spinocerebellar Ataxia 1, SCA1). In particular, we investigate the mitochondrial oxidative metabolism in the cerebellum of transgenic SCA1 mice focusing our studies on the progressive dysfunction of Purkinje cells (PC). Histochemical examination showed a cytochrome‐c‐oxidase (COX) deficiency in PC of TG‐mice, the oxidative defect being more prominent in older mice, in which the percentage of COX‐deficient PC was up to 30%. Using a laser‐microdissector, we evaluated the mitochondrial DNA content on selectively isolated COX‐competent and COX‐deficient PC by quantitative PCR and we found mtDNA depletion in those with oxidative dysfunction. In conclusion, the selective oxidative metabolism defect, observed in neuronal PC expressing mutant ataxin, represents an early pathogenetic step of the PC degeneration in SCA1 disease.