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 journalArticle

1 Citation (Scopus)

Abstract

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
Volume116
DOIs
StatePublished - Aug 1 2018

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Spinocerebellar Ataxias
Purkinje Cells
Ataxia
Cyclic AMP-Dependent Protein Kinases
Phosphorylation
Ataxin-1
Neurodegenerative Diseases
Serine
Catalytic Domain
Phosphotransferases
Pharmacology
Neurons

Keywords

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

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Pérez Ortiz, J. M., Mollema, N., Toker, N., Adamski, C. J., O'Callaghan, B., Duvick, L., ... Lagalwar, S. (2018). Reduction of protein kinase A-mediated phosphorylation of ATXN1-S776 in Purkinje cells delays onset of Ataxia in a SCA1 mouse model. Neurobiology of Disease, 116, 93-105. https://doi.org/10.1016/j.nbd.2018.05.002

Reduction of protein kinase A-mediated phosphorylation of ATXN1-S776 in Purkinje cells delays onset of Ataxia in a SCA1 mouse model. / Pérez Ortiz, Judit M.; Mollema, Nissa; Toker, Nicholas; Adamski, Carolyn J.; O'Callaghan, Brennon; Duvick, Lisa; Friedrich, Jillian; Walters, Michael A.; Strasser, Jessica M; Hawkinson, Jon E.; Zoghbi, Huda Y.; Henzler, Christine; Orr, Harry T; Lagalwar, Sarita.

In: Neurobiology of Disease, Vol. 116, 01.08.2018, p. 93-105.

Research output: Contribution to journalArticle

Pérez Ortiz, JM, Mollema, N, Toker, N, Adamski, CJ, O'Callaghan, B, Duvick, L, Friedrich, J, Walters, MA, Strasser, JM, Hawkinson, JE, Zoghbi, HY, Henzler, C, Orr, HT & Lagalwar, S 2018, 'Reduction of protein kinase A-mediated phosphorylation of ATXN1-S776 in Purkinje cells delays onset of Ataxia in a SCA1 mouse model', Neurobiology of Disease, vol. 116, pp. 93-105. https://doi.org/10.1016/j.nbd.2018.05.002
Pérez Ortiz, Judit M. ; Mollema, Nissa ; Toker, Nicholas ; Adamski, Carolyn J. ; O'Callaghan, Brennon ; Duvick, Lisa ; Friedrich, Jillian ; Walters, Michael A. ; Strasser, Jessica M ; Hawkinson, Jon E. ; Zoghbi, Huda Y. ; Henzler, Christine ; Orr, Harry T ; Lagalwar, Sarita. / Reduction of protein kinase A-mediated phosphorylation of ATXN1-S776 in Purkinje cells delays onset of Ataxia in a SCA1 mouse model. In: Neurobiology of Disease. 2018 ; Vol. 116. pp. 93-105.
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abstract = "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.",
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AU - Pérez Ortiz, Judit M.

AU - Mollema, Nissa

AU - Toker, Nicholas

AU - Adamski, Carolyn J.

AU - O'Callaghan, Brennon

AU - Duvick, Lisa

AU - Friedrich, Jillian

AU - Walters, Michael A.

AU - Strasser, Jessica M

AU - Hawkinson, Jon E.

AU - Zoghbi, Huda Y.

AU - Henzler, Christine

AU - Orr, Harry T

AU - Lagalwar, Sarita

PY - 2018/8/1

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N2 - 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.

AB - 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.

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KW - Cerebellum

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KW - SCA1

KW - cAMP-dependent protein kinase

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