Between Dec 19, 2024 and Jan 2, 2025, datasets can be submitted to DRUM but will not be processed until after the break. Staff will not be available to answer email during this period, and will not be able to provide DOIs until after Jan 2. If you are in need of a DOI during this period, consider Dryad or OpenICPSR. Submission responses to the UDC may also be delayed during this time.

Browsing by Subject "Ataxin-1"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Partial Tip60 loss slows cerebellar degeneration in a Spinocerebellar Ataxia Type 1 (SCA1) mouse model.
    (2009-07) Gehrking, Kristin Marie
    Spinocerebellar ataxia type 1 (SCA1) is one of nine dominantly inherited neurodegenerative diseases caused by polyglutamine tract expansion. In SCA1, the expanded polyglutamine tract is in the ataxin-1 (ATXN1) protein. Increased polyglutamine tract length results in earlier disease onset and greater disease severity, which is largely due to cerebellar Purkinje cell degeneration. ATXN1 is part of an in vivo complex with the nuclear receptor (retinoid acid receptor-related orphan receptor alpha [ROR-alpha]) and acetyltransferase (tat-interactive protein 60 kD [Tip60]). ATXN1 and Tip60 interact directly; however, the significance of this interaction is unclear. To test the effect of partial Tip60 loss on SCA1 disease progression, I developed a mutant ATXN1[82Q]/+:Tip60+/- mouse model. Partial Tip60 loss increased ROR-alpha, Rora, and ROR-alpha-mediated gene expression and delayed ATXN1[82]-mediated cerebellar degeneration during midstage disease progression. I also compared ATXN1[82Q]/+ phenotypes between different genetic background strains. Finally in vitro data suggested an ATXN1 polyglutamine length effect on Tip60 acetyltransferase activity. In additional to highlighting genetic background modulation in SCA1 disease, these results suggest a specific temporal role for Tip60 during disease progression and a putative role for Tip60 acetylation in SCA1 disease progression.
  • Thumbnail Image
    Item
    Regulation and subcellular compartmentalization of ataxin-1 phosphorylation at Serine776.
    (2011-03) Lai, Shaojuan
    Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant cerebellar ataxia caused by the expansion of a CAG repeat encoding an abnormally long polyglutamine tract in Ataxin-1 protein. Although many studies demonstrate that subcellular distribution of Ataxin-1 and protein folding/degradation pathways modulate neurodegeneration, the mechanism of pathogenesis is not completely understood. Phosphorylation of Ataxin-1 at Serine776 (S776) was previously shown to regulate Ataxin-1's functions and SCA1 pathogenicity. In addition, mice expressing human wild type Ataxin-1-[30Q] with a mutation replacing S776 with a phosphomimicking aspartic acid show similar SCA1 pathology as Ataxin-1-[82Q] mice. Here I investigated the mechanism by which phosphorylation of Ataxin-1 at S776 is regulated. I found in the cerebellum a large proportion of Ataxin-1 is phosphorylated at S776 with phosphorylated S776 enriched in the nucleus. While the kinase activity for Ataxin-1 at S776 is localized to the cerebellar cytoplasm, the phosphatase activity is restricted to the nucleus. PP2A was shown to be the phosphatase for phosphorylated S776 Ataxin-1 (Ataxin-1-pS776). 14-3-3, a protein enriched in the cytoplasm, blocks dephosphorylation of Ataxin-1-pS776 by PP2A in the cytoplasm and may affect the shuttling of Ataxin-1 to the nucleus. This work suggests that Ataxin-1 after it is phosphorylated in the cytoplasm, shuttles to the nucleus where it is dephosphorylated by PP2A. The separation of phosphorylation and dephosphorylation of S776-Ataxin-1 into two subcellular compartments may suggest that they regulate different Ataxin-1 functions in different subcellular compartments.