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 language | English (US) |
---|---|
Pages (from-to) | 93-105 |
Number of pages | 13 |
Journal | Neurobiology of Disease |
Volume | 116 |
DOIs | |
State | Published - Aug 2018 |
Bibliographical note
Funding Information:This research was supported NIH Grant RO1-NS045667 and a National Ataxia Foundation Pioneer Award (HTO) ; R37-NS027699 and IDDRC U54HD083092 (HYZ); National Ataxia Foundation Fellowship Research Awards (NM & SL); and a NIH/NRSA F31-NS084540 (JMPO).
Publisher Copyright:
© 2018 The Authors
Keywords
- ATXN1-S776
- Ataxia
- Ataxin-1
- Cerebellum
- PKA
- Phosphorylation
- Polyglutamine
- Protein stability
- Purkinje cells
- SCA1
- cAMP-dependent protein kinase