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

卷:116

Article

Ortiz, Judit M. Perez^1,2  Mollema, Nissa^1,3  Toker, Nicholas⁴  Adamski, Carolyn J.^5,6  O'Callaghan, Brennon^1,3  Duvick, Lisa^1,3  Friedrich, Jillian^1,3  Walters, Michael A.⁷  Strasser, Jessica⁷  Hawkinson, Jon E.⁷  Zoghbi, Huda Y.^5,6  Henzler, Christine⁸  Orr, Harry T.^1,3  Lagalwar, Sarita^1,3,4 

[1] Univ Minnesota, Inst Translat Neurosci, Minneapolis, MN USA

[2] Univ Minnesota, Grad Program Neurosci, Minneapolis, MN USA

[3] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA

[4] Skidmore Coll, Neurosci Program, 815 N Broadway, Saratoga Springs, NY 12866 USA

[5] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA

[6] Baylor Coll Med, Howard Hughes Med Inst, Dept Mol & Human Genet, Houston, TX 77030 USA

[7] Univ Minnesota, Inst Therapeut Discovery & Dev, Dept Med Chem, Minneapolis, MN 55455 USA

[8] Univ Minnesota, Minnesota Supercomp Inst, RISS Bioinformat, Minneapolis, MN USA

关键词: SCA1;    Purkinje cells;    Ataxia;    Phosphorylation;    ATXN1-5776;    cAMP-dependent protein kinase;    PKA;    Ataxin-1;    Cerebellum;    Polyglutamine;    Protein stability;   

DOI  :  10.1016/j.nbd.2018.05.002

来源: Elsevier

【 摘 要 】

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 PICA catalytic subunit C alpha 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 PICA-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.

【 授权许可】

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