Purkinje cell COX deficiency and mtDNA depletion in an animal model of spinocerebellar ataxia type 1

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 COXdeficient 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. K E Y W O R D Slaser microdissector, mitochondria, mitochondrial DNA depletion, oxidative damage, Purkinje cell, spinocerebellar ataxia type 1, transgenic mice

Neuronal metabolic rewiring promotes resilience to neurodegeneration caused by mitochondrial dysfunction

“…This neuronal population is particularly vulnerable to mitochondrial dysfunction, as their selective degeneration in mice is sufficient to reproduce many of the motor symptoms that characterize spinocerebellar ataxia in humans (16,47,48). Transgenic mouse models bearing mutated genes, which are associated with human spinocerebellar ataxia, have also been reported to have mitochondrial dysfunction (49,50), emphasizing the importance of investigating the consequences of OXPHOS deficiency in PNs. For this reason, effective methods to properly isolate and study this unique neuronal population are of particular interest.…”

Hippocampal mitochondrial dysfunction and psychiatric-relevant behavioral deficits in spinocerebellar ataxia 1 mouse model

“…In addition to hippocampal atrophy and the related behavioral deficits, we also identified corresponding mitochondrial dysfunction in the hippocampus (but not in the cerebellum) of the young SCA1 mice. Although mitochondrial dysfunction comprises one of a number of common pathological mechanisms shared by various neurodegenerative diseases 19 , it has been studied only rarely in spinocerebellar ataxias focusing exclusively on cerebellar tissue/cells [23][24][25] . The fact that we did not determine any mitochondrial dysfunction in the cerebellum contradicts the results of previous studies 23, 24 .…”

DNA repair deficiency in neuropathogenesis: when all roads lead to mitochondria

“…However, apoptosis does not seem to be involved in PC degeneration. While levels of brain-derived mtDNA are not different between SCA1 and control mice, mtDNA levels are significantly reduced in cerebellum of SCA1 mice [86].…”