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 major challenge in the search for therapeutics and is the focus of the research outlined in this application for continued support. )

Public Health Relevance

We hypothesize that distinct cellular pathways underlie the two stages of SCA1 disease. 1) The S776/RBM17-mediated disease initiation early progression (pathogenesis), and 2) polyglutamine, age-related late progression. The long-term goal of this work is to use information obtained about these pathways to identify novel avenues for therapeutic development. )

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS022920-25
Application #
8417722
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Gwinn, Katrina
Project Start
1986-08-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
25
Fiscal Year
2013
Total Cost
$428,210
Indirect Cost
$144,627
Name
University of Minnesota Twin Cities
Department
Pathology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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 89:1194-207
Öz, Gülin; Kittelson, Emily; Demirgöz, Döne et al. (2015) Assessing recovery from neurodegeneration in spinocerebellar ataxia 1: Comparison of in vivo magnetic resonance spectroscopy with motor testing, gene expression and histology. Neurobiol Dis 74:158-66
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
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
Orr, Harry T (2012) Cell biology of spinocerebellar ataxia. J Cell Biol 197:167-77
Ingram, Melissa A C; Orr, Harry T; Clark, H Brent (2012) Genetically engineered mouse models of the trinucleotide-repeat spinocerebellar ataxias. Brain Res Bull 88:33-42
Orr, Harry T (2012) Polyglutamine neurodegeneration: expanded glutamines enhance native functions. Curr Opin Genet Dev 22:251-5

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