Spinocerebellar ataxia type 7 (SCA7) is an inherited neurological disorder characterized by cerebellar and retinal degeneration. SCA7 is caused by CAG/polyglutamine (polyQ) repeat expansions in the ataxin-7 gene. In the last funding cycle, we proposed to determine the mechanistic basis of SCA7 disease pathogenesis, as a prelude to therapy development. To achieve this goal, we created novel mouse models for SCA7, which we used to define the cellular basis of SCA7 neurodegeneration and to delineate a complex epigenetic pathway for ataxin-7 transcription regulation. During this time frame, we gained insight into the nature of polyQ-ataxin-7 transcriptional dysregulation, originally uncovered in ou SCA7 mouse model. Our discovery of ataxin-7 as a core component of the STAGA co-activator complex has led to a model for SCA7 involving altered normal function of this disease protein. To better understand the basis for polyQ-expanded ataxin-7 interference with STAGA, we turned to yeast, as Sgf73, the yeast orthologue of ataxin-7, is a core component of the yeast SAGA complex, and discovered that loss-of-function of Sgf73 yields an unexpected phenotype in yeast: dramatic lifespan extension. We also found evidence for altered chromatin regulation in this aging pathway, and documented changes in chromatin regulation in SCA7 mice, suggesting an epigenetic underpinning to SCA7 neurodegeneration. We demonstrated a genetic and functional interaction between Sgf73 and Sir2, the original member of a family of proteins known as the "sirtuins", and noted a physical interaction between ataxin-7 and mammalian Sirt1. In this renewal proposal, we outline a series of experiments to define SCA7 epigenetic dysregulation by identifying gene targets and pathways involved in the Sgf73 loss-of-function lifespan extension phenotype in yeast and in neurodegeneration phenotypes in SCA7 mice. Reversal of SCA7 neurodegeneration in mice, through the use of our recently developed PrP-floxed-SCA7-92Q BAC mice in crosses with CAGGS-Cre-ERTM mice, will be used to determine if epigenetic alterations contribute to SCA7 disease pathogenesis or are merely coincident with the SCA7 disease process. In a second set of studies, we will examine the role of Sirt1 dysfunction in SCA7 by testing if altered USP22 deubiquitination function affects Sirt1 stability and activity, an if Sirt1 over-expression can rescue retinal and cerebellar degeneration in SCA7 mice. We will also catalogue gene expression alterations in the CNS of SCA7 transgenic mice, and determine if Sirt1 over-expression can restore disease-associated transcriptional abnormalities to define Sirt1 substrate targets involved in SCA7 disease pathogenesis. These provocative experiments will determine how alteration of ataxin-7 normal function yields SCA7, and will provide insights for therapy development for this disorder.
Spinocerebellar ataxia type 7 (SCA7) is an inherited polyglutamine neurodegenerative disorder characterized by cerebellar and retinal degeneration, resulting from transcriptional dysregulation involving an alteration of ataxin-7's normal function as a member of two chromatin remodeling complexes. In the last funding cycle, we defined the cellular basis of SCA7 neurodegeneration, and documented substantial evidence for transcriptional and epigenetic dysregulation in yeast made null for the ataxin-7 orthologue Sgf73 and in SCA7 mice, thereby uncovering physical and functional interactions between Sgf73 and Sir2, the original member of a family of proteins known as the sirtuins, and ataxin-7 and mammalian Sirt1. In this renewal proposal, we propose to define the basis and significance of epigenetic dysregulation in SCA7 by performing hypothesis-driven and discovery-based studies in yeast and in SCA7 mice, by defining the mechanistic basis of Sirt1 dysfunction, and by determining, through in vivo experimentation, if Sirt1 dysfunction contributes to SCA7 neurodegeneration, as the ultimate goal of our proposed studies will be to identify targets and pathways for therapy development.
|Guyenet, Stephan J; Mookerjee, Shona S; Lin, Amy et al. (2015) Proteolytic cleavage of ataxin-7 promotes SCA7 retinal degeneration and neurological dysfunction. Hum Mol Genet 24:3908-17|
|Ramachandran, Pavitra S; Boudreau, Ryan L; Schaefer, Kellie A et al. (2014) Nonallele specific silencing of ataxin-7 improves disease phenotypes in a mouse model of SCA7. Mol Ther 22:1635-42|
|Ramachandran, Pavitra S; Bhattarai, Sajag; Singh, Pratibha et al. (2014) RNA interference-based therapy for spinocerebellar ataxia type 7 retinal degeneration. PLoS One 9:e95362|
|Ward, Jacqueline M; La Spada, Albert R (2014) Identification of the SCA21 disease gene: remaining challenges and promising opportunities. Brain 137:2626-8|
|McCormick, Mark A; Mason, Amanda G; Guyenet, Stephan J et al. (2014) The SAGA histone deubiquitinase module controls yeast replicative lifespan via Sir2 interaction. Cell Rep 8:477-86|
|Furrer, Stephanie A; Waldherr, Sarah M; Mohanachandran, Mathini S et al. (2013) Reduction of mutant ataxin-7 expression restores motor function and prevents cerebellar synaptic reorganization in a conditional mouse model of SCA7. Hum Mol Genet 22:890-903|
|Nakamura, Yoko; Tagawa, Kazuhiko; Oka, Tsutomu et al. (2012) Ataxin-7 associates with microtubules and stabilizes the cytoskeletal network. Hum Mol Genet 21:1099-110|
|Furrer, Stephanie A; Mohanachandran, Mathini S; Waldherr, Sarah M et al. (2011) Spinocerebellar ataxia type 7 cerebellar disease requires the coordinated action of mutant ataxin-7 in neurons and glia, and displays non-cell-autonomous bergmann glia degeneration. J Neurosci 31:16269-78|
|Sopher, Bryce L; Ladd, Paula D; Pineda, Victor V et al. (2011) CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense noncoding RNA. Neuron 70:1071-84|
|Guyenet, Stephan J; Furrer, Stephanie A; Damian, Vincent M et al. (2010) A simple composite phenotype scoring system for evaluating mouse models of cerebellar ataxia. J Vis Exp :|
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