Spinocerebellar ataxia type 1 (SCA1) is one of a series of autosomal dominant cerebellar ataxia. SCA1 patients develop gait ataxia, dysarthda and nystagmuso. As the disease progresses other signs of cerebellar and brainstem dysfunction become apparent with death resulting from loss of bulbar function. Neuropathology in SCA1 includes severe loss of cerebellar Purkinje cells. SCA1 is among a group of neurodegenerative disorders caused by an expansion of a CAG triplet repeat encoding a polyglutamine tract within each respective disease protein. Substantial progress has been made towards understanding the molecular basis of SCA1 pathogenesis. However, several critical questions remain for SCA1 and for polyglutamine disorders in general. These, for the most part, relate to the relative importance of the polyglutamine tract vs. its protein context for driving disease. We propose a model of SCA1 pathogenesis in which disease ensues due to a disruption of nuclear architecture and/or function in specific neurons by mutant ataxin-1 (the SCA1 gene product). In this model, there are predicted to be several points at which residues in Jataxin-1 that, along with the polyglutamine tract, would have a critical role in driving the development and progression of disease.
The Aims of this proposal use a genetic approach to test several important aspects of this model in transgenic mice. Understanding the importance of these factors for SCA1 pathogenesis should provide insights for polyglutamine diseases in general.
|Lu, Hsiang-Chih; Tan, Qiumin; Rousseaux, Maxime W C et al. (2017) Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans. Nat Genet 49:527-536|
|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|
|Tan, Qiumin; Yalamanchili, Hari Krishna; Park, Jeehye et al. (2016) Extensive cryptic splicing upon loss of RBM17 and TDP43 in neurodegeneration models. Hum Mol Genet 25:5083-5093|
|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|
|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|
Showing the most recent 10 out of 66 publications