Abstract

Spinocerebellar ataxia type 1 (SCA1) is an untreatable fatal autosomal dominant neurodegenerative disorder caused by the expansion of a glutamine repeat within the SCA1-encoded protein ATXN1. Previous work showed that ATXN1 is modified by phosphorylation at serine residue 776 and this phosphorylation is critical for mutant ATXN1 to cause disease. Recent evidence form the parent project indicates that PKA mediates the phosphorylation of serine 776. This application, in response to Notice Number (NOT-OD-09-058), """"""""NIH Announces the Availability of Recovery Act Funds for Competitive Revisions Applications"""""""" is a request to undertake a high-throughput screen and lead compound optimization for inhibitors of PKA-mediated phosphorylation of serine 776.

Public Health Relevance

In undertaking these studies we are taking an important step towards developing reagents to test the hypothesis that a small molecule inhibitor of serine phosphorylation reaction could provide a novel, effective treatment for SCA1.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS045667-07S1
Application #
7808678
Study Section
Special Emphasis Panel (ZRG1-MDCN-T (95))
Program Officer
Gwinn, Katrina
Project Start
2003-08-15
Project End
2012-02-29
Budget Start
2009-09-30
Budget End
2012-02-29
Support Year
7
Fiscal Year
2009
Total Cost
$1,060,867
Indirect Cost

  Institution

Name
University of Minnesota Twin Cities
Department
Pathology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455

  Publications

Pérez Ortiz, Judit M; Mollema, Nissa; Toker, Nicholas et al. (2018) Reduction of protein kinase A-mediated phosphorylation of ATXN1-S776 in Purkinje cells delays onset of Ataxia in a SCA1 mouse model. Neurobiol Dis 116:93-105
Keiser, Megan S; Kordasiewicz, Holly B; McBride, Jodi L (2016) Gene suppression strategies for dominantly inherited neurodegenerative diseases: lessons from Huntington's disease and spinocerebellar ataxia. Hum Mol Genet 25:R53-64
Rubinsztein, David C; Orr, Harry T (2016) Diminishing return for mechanistic therapeutics with neurodegenerative disease duration?: There may be a point in the course of a neurodegenerative condition where therapeutics targeting disease-causing mechanisms are futile. Bioessays 38:977-80
Ingram, Melissa; Wozniak, Emily A L; Duvick, Lisa et al. (2016) Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways. Neuron 89:1194-1207
Keiser, Megan S; Kordower, Jeffrey H; Gonzalez-Alegre, Pedro et al. (2015) Broad distribution of ataxin 1 silencing in rhesus cerebella for spinocerebellar ataxia type 1 therapy. Brain 138:3555-66
Cvetanovic, M; Ingram, M; Orr, H et al. (2015) Early activation of microglia and astrocytes in mouse models of spinocerebellar ataxia type 1. Neuroscience 289:289-99
Dahlin, Jayme L; Walters, Michael A (2014) The essential roles of chemistry in high-throughput screening triage. Future Med Chem 6:1265-90
Nelson, David L; Orr, Harry T; Warren, Stephen T (2013) The unstable repeats--three evolving faces of neurological disease. Neuron 77:825-43
Ebner, Blake A; Ingram, Melissa A; Barnes, Justin A et al. (2013) Purkinje cell ataxin-1 modulates climbing fiber synaptic input in developing and adult mouse cerebellum. J Neurosci 33:5806-20
Orr, Harry T (2012) Cell biology of spinocerebellar ataxia. J Cell Biol 197:167-77

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