Spinocerebellar Ataxia Type 1 (SCA1) Cell Models Display Widespread Mitochondrial and Extra-Nuclear Alterations.

Ataxin-1 (ATXN1) is a nuclear-cytoplasmic shuttling protein, which, when expanded in its polyglutamine coding stretch, causes the progressive neurodegenerative disease Spinocerebellar Ataxia Type 1 (SCA1). While the role of nuclear ATXN1 as a repressor of transcription and regulator of splicing is well studied, its potential cytoplasmic role is more ambiguous. We previously demonstrated mitochondrial dysfunction- including altered respiration and enhanced oxidative stress- is associated with early SCA1 pathogenesis in mice. Moreover, intervention with the electron transport chain substrate succinic acid ameliorated Purkinje cell atrophy and cerebellar behavioral deficits. We now hypothesize that mitochondrial dysfunction in SCA1 may be at least partially due to cytoplasmic interactions between ATXN1 and mitochondria, rather than a result of mutant ATXN1's altered nuclear function. In order to characterize the extent of mitochondrial dysfunction due to mutant ATXN1, we turned to cerebellar-derived Daoy cells which endogenously express human wild type ATXN1. Our SCA1 Daoy model stably over-express phosphorylation-prone, nuclear-aggregating ATXN1[82]. Despite the short lifespan (~ 33 h), Daoy SCA1 cells reveal gross morphological, compositional, and physiological deficits. Conversely, expression in Daoy of a phosphorylation-resistant, cytoplasm-degradable, non-aggregating ATXN1 (ATXN1[82Q-A776]) selectively resulted in intermediate physiological phenotypes and altered mitochondrial protein composition. Finally, our meta-analysis of previously published data supports direct interactions between mutant polyglutamine-expanded ATXN1 and mitochondrial proteins involved in apoptosis, oxidative phosphorylation, composition, and transcription. Our data therefore suggest that irrespective of a disease context and ATXN1[82Q] nuclear aggregation, mitochondrial deficits occur. Overall, the results of this study show mutant ATXN1 can affect metabolic processes outside of its deleterious effect on transcription and splicing, and highlights its multifaceted and multicompartmental function.