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| Status |
Public on May 31, 2019 |
| Title |
Reduction of Protein Kinase A-mediated Phosphorylation of ATXN1-S776 in Purkinje Cells Delays Onset of Ataxia in a SCA1 Mouse Model. |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Cerebellar mRNA profiles of 8-9 week old wild type (WT), Atxn1[82Q] knockin and Atxn1[82Q]CαLoxM120A mice were generated by deep sequencing, 5 replicates per treatment, using Illumina HiSeq2500.
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| Contributor(s) |
Henzler C, Orr HT, Lagalwar S |
| Citation missing |
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| |
| Submission date |
May 23, 2018 |
| Last update date |
May 31, 2019 |
| Contact name |
Harry T Orr |
| E-mail(s) |
orrxx002@umn.edu
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| Organization name |
University of Minnesota
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| Department |
Laboratory Medicine and Pathology
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| Street address |
2101 6th Strreet SE
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| City |
Minneapolis |
| State/province |
MN |
| ZIP/Postal code |
55455 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (15)
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| Relations |
| BioProject |
PRJNA472754 |
| SRA |
SRP148782 |
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