Reduction of protein kinase A-mediated phosphorylation of ATXN1-S776 in Purkinje cells delays onset of Ataxia in a SCA1 mouse model
2018; Elsevier BV; Volume: 116; Linguagem: Inglês
10.1016/j.nbd.2018.05.002
ISSN1095-953X
AutoresJudit Perez 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,
Tópico(s)DNA Repair Mechanisms
ResumoSpinocerebellar 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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