Reduction of protein kinase A-mediated phosphorylation of ATXN1-S776 in Purkinje cells delays onset of Ataxia in a SCA1 mouse model

Judit M. Pérez Ortiz, Nissa Mollema, Nicholas Toker, Carolyn J. Adamski, Brennon O'Callaghan, Lisa Duvick, Jillian Friedrich, Michael A. Walters, Jessica M Strasser, Jon E. Hawkinson, Huda Y. Zoghbi, Christine Henzler, Harry T Orr, Sarita Lagalwar

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Spinocerebellar ataxia type 1 (SCA1) is a polyglutamine (polyQ) repeat neurodegenerative disease in which a primary site of pathogenesis are cerebellar Purkinje cells. In addition to polyQ expansion of ataxin-1 protein (ATXN1), phosphorylation of ATXN1 at the serine 776 residue (ATXN1-pS776) plays a significant role in protein toxicity. Utilizing a biochemical approach, pharmacological agents and cell-based assays, including SCA1 patient iPSC-derived neurons, we examine the role of Protein Kinase A (PKA) as an effector of ATXN1-S776 phosphorylation. We further examine the implications of PKA-mediated phosphorylation at ATXN1-S776 on SCA1 through genetic manipulation of the PKA catalytic subunit Cα in Pcp2-ATXN1[82Q] mice. Here we show that pharmacologic inhibition of S776 phosphorylation in transfected cells and SCA1 patient iPSC-derived neuronal cells lead to a decrease in ATXN1. In vivo, reduction of PKA-mediated ATXN1-pS776 results in enhanced degradation of ATXN1 and improved cerebellar-dependent motor performance. These results provide evidence that PKA is a biologically important kinase for ATXN1-pS776 in cerebellar Purkinje cells.

Original languageEnglish (US)
Pages (from-to)93-105
Number of pages13
JournalNeurobiology of Disease
StatePublished - Aug 2018

Bibliographical note

Funding Information:
This research was supported NIH Grant RO1-NS045667 and a National Ataxia Foundation Pioneer Award (HTO) ; R37-NS027699 and IDDRC U54HD083092 (HYZ); National Ataxia Foundation Fellowship Research Awards (NM & SL); and a NIH/NRSA F31-NS084540 (JMPO).

Publisher Copyright:
© 2018 The Authors


  • ATXN1-S776
  • Ataxia
  • Ataxin-1
  • Cerebellum
  • PKA
  • Phosphorylation
  • Polyglutamine
  • Protein stability
  • Purkinje cells
  • SCA1
  • cAMP-dependent protein kinase


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