Spinocerebellar ataxia type 1 (SCA1) is one of nine fatal inherited neurodegenerative diseases caused by expansion of an inframe CAG trinucleotide repeat. Each repeat tract encodes a stretch of glutamine residues in the affected protein, in the case of SCA1 the protein is ataxin-1 (ATXN1). Symptoms of SCA1 include loss of motor coordination and balance, slurred speech, swallowing difficulty, spasticity, and some cognitive impairment. A characteristic feature of SCA1 pathology is atrophy and eventual loss of Purkinje cells from the cerebellar cortex. Like many neurodegenerative disorders, SCA1 is typically a late onset disease suggesting that physiological changes due to aging contribute to the onset of the disease. There is currently no effective treatment. Thus, identifying signaling pathways and cellular mediators of SCA1 onset and progression remain a application for continued support. The major aims of this competitive renewal, are: 1) dissecting the signaling pathway(s) and their components that regulate phosphorylation of ATXN1-S776 in cerebellar Purkinje cells in vivo, and 2) assessing whether S776 and its phosphorylation plays a role in mutant ATXN1-induced disease in regions of the brain in addition to Purkinje cells. Most notably the Bulbar signs affecting swallowing, due to pathology in the brainstem

Public Health Relevance

We hypothesize that phosphorylation of S776 (residue number based on human ATXN1 with 30Q), is a target for therapeutic development. One aim of this project will undertake a dissection of the ATXN1-S776 phosphorylation signaling pathway in vivo -- not only to better understand the biology of ATXN1 and SCA1 but to also identify additional targets for therapeutic intervention. The second goal will be to examine the extent to which the pS776 pathway contributes to SCA1 in regions of the brain beyond the cerebellum, i.e. does S776 have role in SCA1 phenotypes in addition to the cerebellar ataxia?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Gwinn, Katrina
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University of Minnesota Twin Cities
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PĂ©rez 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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