Ataxin-1 regulates the cerebellar bioenergetics proteome through the GSK3β-mTOR pathway which is altered in Spinocerebellar ataxia type 1 (SCA1).

Abstract

A polyglutamine expansion within the ataxin-1 protein (ATXN1) underlies spinocerebellar ataxia type-1 (SCA1), a neurological disorder mainly characterized by ataxia and cerebellar deficits. In SCA1, both loss and gain of ATXN1 biological functions contribute to cerebellar pathogenesis. However, the critical ATXN1 functions and pathways involved remain unclear. To further investigate the early signalling pathways regulated by ATXN1, we performed an unbiased proteomic study of the Atxn1-KO 5-week-old mice cerebellum. Here, we show that lack of ATXN1 expression induces early alterations in proteins involved in glycolysis [pyruvate kinase, muscle, isoform 1 protein (PKM-i1), citrate synthase (CS), glycerol-3-phosphate dehydrogenase 2 (GPD2), glucose-6-phosphate isomerase (GPI), alpha -: enolase (ENO1)], ATP synthesis [CS, Succinate dehydrogenase complex,subunit A (SDHA), ATP synthase subunit d, mitochondrial (ATP5H)] and oxidative stress [peroxiredoxin-6 (PRDX6), aldehyde dehydrogenase family 1, subfamily A1, 10-formyltetrahydrofolate dehydrogenase]. In the SCA1 mice, several of these proteins (PKM-i1, ATP5H, PRDX6, proteome subunit A6) were down-regulated and ATP levels decreased. The underlying mechanism does not involve modulation of mitochondrial biogenesis, but dysregulation of the activity of the metabolic regulators glycogen synthase kinase 3B (GSK3β), decreased in Atxn1-KO and increased in SCA1 mice, and mechanistic target of rapamycin (serine/threonine kinase) (mTOR), unchanged in the Atxn1-KO and decreased in SCA1 mice cerebellum before the onset of ataxic symptoms. Pharmacological inhibition of GSK3β and activation of mTOR in a SCA1 cell model ameliorated identified ATXN1-regulated metabolic proteome and ATP alterations. Taken together, these results point to an early role of ATXN1 in the regulation of bioenergetics homeostasis in the mouse cerebellum. Moreover, data suggest GSK3β and mTOR pathways modulate this ATXN1 function in SCA1 pathogenesis that could be targeted therapeutically prior to the onset of disease symptoms in SCA1 and other pathologies involving dysregulation of ATXN1 functions.