A novel function of ataxin-1 in the modulation of PP2A activity is dysregulated in the spinocerebellar ataxia type 1

Ivelisse Sánchez, Patricia Pinol, Marc Corral-Juan, Massimo Pandolfo, Antoni Matilla-Dueñas

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    10 Citations (Scopus)


    An expansion of glutamines within the human ataxin-1 protein underlies spinocerebellar ataxia type 1 (SCA1), a dominantly inherited neurodegenerative disorder characterized by ataxia and loss of cerebellar Purkinje neurons. Although the mechanisms linking the mutation to the disease remain unclear, evidence indicates that it involves a combination of both gain and loss of functions of ataxin-1. We previously showed that the mutant ataxin-1 interacts with Anp32a, a potent and selective PP2A inhibitor, suggesting a role of PP2A in SCA1. Herein,wefound anewfunction of ataxin-1: the modulation of Pp2a activity and the regulation of its holoenzyme composition, with the polyglutamine mutation within Atxn1 altering this function in theSCA1mouse cerebellum before disease onset. We show that ataxin-1 enhances Pp2a-bβ expression and down-regulates Anp32a levels without affecting post-translationalmodifications of Pp2a catalytic subunit (Pp2a-c) known to regulate Pp2a activity. In contrast, mutant Atxn1 induces a decrease in Y307-phosphorylation in Pp2a-c, known to enhance its activity, while reducing Pp2a-b expression and inhibiting Anp32a levels. qRT-PCR and chromatin immunoprecipitation analyses show that ataxin-1-mediated regulations of the Pp2a-bβ subunit, specifically bb2, and of Anp32a occur at the transcriptional level. The Pp2a pathway alterations were confirmed by identified phosphorylation changes of theknown Pp2a-substrates, Erk2 and Gsk3β. Similarly, mutant ataxin-1-expressing SH-SY5Y cells exhibit abnormal neuritic morphology, decreased levels of both PP2A-Bβ and ANP32A, and PP2A pathway alterations, all of which are ameliorated by overexpressing ANP32A. Our results point to dysregulation of this newly assigned function of ataxin-1 in SCA1 uncovering new potential targets for therapy. © The Author 2013. Published by Oxford University Press. All rights reserved.
    Original languageEnglish
    Article numberddt197
    Pages (from-to)3425-3437
    JournalHuman Molecular Genetics
    Issue number17
    Publication statusPublished - 1 Sep 2013


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