Phosphorylation of ATXN1 at Ser776 in the cerebellum

Nathan D. Jorgensen, J. Michael Andresen, Sara Lagalwar, Ben Armstrong, Sam Stevens, Courtney E. Byam, Lisa A. Duvick, Shaojuan Lai, Paymaan Jafar-Nejad, Huda Y. Zoghbi, H. Brent Clark, Harry T. Orr

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Abstract

Spinocerebellar ataxia type 1 (SCA1) is one of nine inherited neurodegenerative disorders caused by a mutant protein with an expanded polyglutamine tract. Phosphorylation of ataxin-1 (ATXN1) at serine 776 is implicated in SCA1 pathogenesis. Previous studies, utilizing transfected cell lines and a Drosophila photoreceptor model of SCA1, suggest that phosphorylating ATXN1 at S776 renders it less susceptible to degradation. This work also indicated that oncogene from AKR mouse thymoma (Akt) promotes the phosphorylation of ATXN1 at S776 and severity of neurodegeneration. Here, we examined the phosphorylation of ATXN1 at S776 in cerebellar Purkinje cells, a prominent site of pathology in SCA1. We found that while phosphorylation of S776 is associated with a stabilization of ATXN1 in Purkinje cells, inhibition of Akt either in vivo or in a cerebellar extract-based phosphorylation assay did not decrease the phosphorylation of ATXN1-S776. In contrast, immunodepletion and inhibition of cyclic AMP-dependent protein kinase decreased phosphorylation of ATXN1-S776. These results argue against Akt as the in vivo kinase that phosphorylates S776 of ATXN1 and suggest that cyclic AMP-dependent protein kinase is the active ATXN1-S776 kinase in the cerebellum.

Original languageEnglish (US)
Pages (from-to)675-686
Number of pages12
JournalJournal of Neurochemistry
Volume110
Issue number2
DOIs
StatePublished - Jul 1 2009

Keywords

  • Ataxin-1
  • Cyclic AMP-dependent protein kinase
  • Oncogene from AKR mouse thymoma
  • Phosphorylation
  • Spinocerebellar ataxia type 1

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    Jorgensen, N. D., Andresen, J. M., Lagalwar, S., Armstrong, B., Stevens, S., Byam, C. E., Duvick, L. A., Lai, S., Jafar-Nejad, P., Zoghbi, H. Y., Clark, H. B., & Orr, H. T. (2009). Phosphorylation of ATXN1 at Ser776 in the cerebellum. Journal of Neurochemistry, 110(2), 675-686. https://doi.org/10.1111/j.1471-4159.2009.06164.x