Abstract
Mitochondrial dysfunction plays a significant role in neurodegenerative disease including ataxias and other movement disorders, particularly those marked by progressive degeneration in the cerebellum. In this study, we investigate the role of mitochondrial oxidative phosphorylation (OXPHOS) deficits in cerebellar tissue of a Purkinje cell-driven spinocerebellar ataxia type 1 (SCA1) mouse. Using RNA sequencing transcriptomics, OXPHOS complex assembly analysis and oxygen consumption assays, we report that in the presence of mutant polyglutamine-expanded ataxin-1, SCA1 mice display deficits in cerebellar OXPHOS complex I (NADH-coenzyme Q oxidoreductase). Complex I genes are upregulated at the time of symptom onset and upregulation persists into late stage disease; yet, functional assembly of complex I macromolecules are diminished and oxygen respiration through complex I is reduced. Acute treatment of postsymptomatic SCA1 mice with succinic acid, a complex II (succinate dehydrogenase) electron donor to bypass complex I dysfunction, ameliorated cerebellar OXPHOS dysfunction, reduced cerebellar pathology and improved motor behavior. Thus, exploration of mitochondrial dysfunction and its role in neurodegenerative ataxias, and warrants further investigation.
Highlights
Spinocerebellar ataxia type 1 (SCA1) is a progressive, autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the ataxin-1 (ATXN1, SCA1) gene that produces a polyglutamine expansion in the coded protein
Reliance of Purkinje neurons on oxidative phosphorylation (OXPHOS) activity is apparent in disorders of global mitochondrial dysfunction [14,15,16,17,18] and OXPHOS complexassociated disorders [14, 19], in which Purkinje neurons are critically vulnerable
Transgenic lines were bred to homozygosity (B05+/+ and A02+/+, referred to here as B05 and A02 for simplicity) and maintained along with wild type mice at the Skidmore College mouse facility in strict accordance with the recommendations established for the care and use of laboratory animals by the National Institute of Health and approved by the Skidmore College Institutional Care and Use Committee (IACUC) (NIH Publications No 8023, revised 1978)
Summary
Spinocerebellar ataxia type 1 (SCA1) is a progressive, autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the ataxin-1 (ATXN1, SCA1) gene that produces a polyglutamine expansion in the coded protein. Pathogenic alleles house 39–82 glutamine and glutamine tract-length indirectly correlates with age of onset [1] likely due to strengthened stability [2,3,4] of expanded ATXN1 protein and altered function in its role as a regulator of gene expression and transcript splicing [5,6,7](reviewed in [2]). The primary site of SCA1 pathogenesis are cerebellar Purkinje neurons, the sole known cell type in which ATXN1 expression is both cytoplasmic and nuclear [8,9,10,11]. With their extensively branched dendritic arbors and long axons, Purkinje neurons require high metabolic activity [12, 13]. Reliance of Purkinje neurons on OXPHOS activity is apparent in disorders of global mitochondrial dysfunction [14,15,16,17,18] and OXPHOS complexassociated disorders [14, 19], in which Purkinje neurons are critically vulnerable
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