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, we found a new function 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 the
SCA1 mouse cerebellum before disease onset. We show that
ataxin-1 enhances Pp2a-bβ expression and down-regulates Anp32a levels without affecting post-translational modifications 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 bβ2, and of Anp32a occur at the transcriptional level. The Pp2a pathway alterations were confirmed by identified phosphorylation changes of the known 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.