Spinocerebellar ataxia type 1 (SCA1) is one of nine fatal inherited neurodegenerative diseases caused by expansion of an in-frame 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 major challenge in the search for therapeutics and is the focus of the research outlined in this application for continued support. The major aims of this competitive renewal are to further examine the role of ATXN1-S776 phosphorylation by examining the impact of altering ATXN1-S776 phosphorylation on polyQexp ATXN1 toxicity the brainstem-medulla, and characterize a novel protective pathway activated by a cholecystokinin receptor 1 (Cck1R) agonist in SCA Purkinje cells.

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 will be to examine the extent to which the pS776 pathway contributes to SCA1 disease in regions of the brain beyond the cerebellum, i.e. does S776 have role in the SCA1 premature lethality phenotype in addition to the cerebellar ataxia? The second aim is characterize a novel protective pathway activated by a cholecystokinin receptor 1 (Cck1R) agonist in SCA Purkinje cells as an important step towards drug development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045667-18
Application #
9924651
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Miller, Daniel L
Project Start
2003-08-15
Project End
2023-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
18
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pathology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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) SCA1-phosphorylation, a regulator of Ataxin-1 function and pathogenesis. Prog Neurobiol 99:179-85

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