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
Judit M Pérez OrtizSarita Lagalwar

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.

Citations

Sep 24, 2020·Expert Opinion on Therapeutic Targets·Andreia Neves-CarvalhoPatrícia Maciel
Apr 20, 2020·Cellular and Molecular Life Sciences : CMLS·Leon Tejwani, Janghoo Lim
Apr 13, 2019·Nature Reviews. Disease Primers·Thomas KlockgetherHenry L Paulson
Apr 28, 2020·Archives of Biochemistry and Biophysics·Consuelo MoriTomás A Santa Coloma
Nov 20, 2020·Cell Death and Differentiation·François Le Guerroué, Richard J Youle
May 26, 2021·Stem Cell Reviews and Reports·Marina P HommersomHans van Bokhoven
Jul 25, 2021·Journal of Molecular Biology·Seppe LeysenJeremy Martin Davis
Nov 27, 2021·Journal of Molecular Neuroscience : MN·Haoyang HuangSarita Lagalwar

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