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

Carolyn J. Adamski¹  Michael A. Walters¹  Christine Henzler¹  Jon E. Hawkinson¹  Nissa Mollema²  Sarita Lagalwar³  Harry T. Orr³  Judit M. Pérez Ortiz⁴  Jessica Strasser⁴  Jillian Friedrich⁴  Huda Y. Zoghbi⁴  Nicholas Toker⁴  Lisa Duvick⁵  Brennon O'Callaghan⁶ 

[1] Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, United States;Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, United States;Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, United States;Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, United States;Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, and Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX, United States;Skidmore College Neuroscience Program, Saratoga Springs, NY, United States;

关键词: SCA1;    Purkinje cells;    Ataxia;    Phosphorylation;    ATXN1-S776;    cAMP-dependent protein kinase;   

DOI  :  

来源: DOAJ

【 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 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.

【 授权许可】

Unknown