Disease relevance of Atxn1

• Transgenic mice carrying the spinocerebellar ataxia type 1 (SCA1) gene, a polyglutamine neurodegenerative disorder, develop ataxia with ataxin-1 localized to aggregates within cerebellar Purkinje cells nuclei [1].
• Thus, these data suggest that this region of ataxin-1 has a role in disease progression [2].
• Here we show that TG2 also crosslinks spinocerebellar ataxia-1 (SCA1) gene product ataxin-1 [3].
• Upon intracerebellar injection, recombinant adeno-associated virus (AAV) vectors expressing short hairpin RNAs profoundly improved motor coordination, restored cerebellar morphology and resolved characteristic ataxin-1 inclusions in Purkinje cells of SCA1 mice [4].
• If given intravenously to mice just after ischemia-reperfusion injury, cardiac Sca1+ cells home selectively to injured myocardium and differentiate spontaneously in situ [5].

Psychiatry related information on Atxn1

• However, Sca1 null mice demonstrate decreased exploratory behavior, pronounced deficits in the spatial version of the Morris water maze test, and impaired performance on the rotating rod apparatus [6].

High impact information on Atxn1

• Moreover, the expression of noncoding (CUG)n expansion transcripts (ataxin 8 opposite strand, ATXN8OS) and the discovery of intranuclear polyglutamine inclusions suggests SCA8 pathogenesis involves toxic gain-of-function mechanisms at both the protein and RNA levels [7].
• 1C2-positive intranuclear inclusions in cerebellar Purkinje and brainstem neurons in SCA8 expansion mice and human SCA8 autopsy tissue result from translation of a polyglutamine protein, encoded on a previously unidentified antiparallel transcript (ataxin 8, ATXN8) spanning the repeat in the CAG direction [7].
• Here we evaluate the ability of RNA interference (RNAi) to inhibit polyglutamine-induced neurodegeneration caused by mutant ataxin-1 in a mouse model of SCA1 [4].
• Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures [8].
• Nuclear matrix preparations demonstrate that ataxin-1 associates with the nuclear matrix in Purkinje and COS cells [8].

Chemical compound and disease context of Atxn1

• Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat which encodes glutamine in the novel protein ataxin-1 [9].

Biological context of Atxn1

• These data suggest that, even with 78 glutamines, prolonged exposure to mutant ataxin-1 at endogenous levels is necessary to produce a neurological phenotype reminiscent of human SCA1 [10].
• Mapping of the Sca1 and pcd genes on mouse chromosome 13 provides evidence that they are different genes [11].
• Here, we show that autophagy is essential for the elimination of aggregated forms of mutant huntingtin and ataxin-1 from the cytoplasmic but not nuclear compartments [12].
• Expression of the Ly-6E.1 (Sca-1) transgene in adult hematopoietic stem cells and the developing mouse embryo [13].
• Depletion of MNCs of either CD11b-positive, CD45R-positive, or Sca-1-positive cells resulted in significant attenuation of endothelium-dependent vasodilation as compared with nondepleted MNCs; however, vasoreactivity was still significantly improved as compared with saline-treated apoE(-/-) mice [14].

Anatomical context of Atxn1

• Herein is reported the existence of nontubular cells that express stem cell antigen-1 (Sca-1) [15].
• Immunocytochemistry was performed to identify the bone marrow origin of the cells in the RPE using antibodies for CD45, Sca-1, and c-kit, as well as the expression of the RPE-specific marker, RPE-65 [16].
• During cerebellar development, there is a transient burst of Sca1 expression at postnatal day 14 when the murine cerebellar cortex becomes physiologically functional [9].
• These results suggest that the normal Sca1 gene, has a role at specific stages of both cerebellar and vertebral column development [9].
• There is also marked expression of Sca1 in mesenchymal cells of the intervertebral discs during development of the spinal column [9].

Associations of Atxn1 with chemical compounds

• Sca-1(+) mononuclear cell populations in culture from samples of bone marrow at 48 hours bound together Ulex Europus-1, and incorporated fluorescent 1,1'-dioctadecyl- 3,3,3,'3'-tetramethylindocarbocyanine perchlorate-labelled acetylated low-density lipoprotein intracellularily, both characteristics of mature endothelium [17].
• Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice [1].
• We also show that muscle contains a population of cells with several characteristics of bone marrow-derived hematopoietic stem cells, including high efflux of the fluorescent dye Hoechst 33342 and expression of the stem cell antigens Sca-1 and c-Kit, although the cells lack the hematopoietic marker CD45 [18].
• We found that a homogeneous cell population expressing high surface levels of stem cell antigen 1 (Sca-1) was able to give rise in vivo to ductal and alveolar structures comprising luminal secretory and basal myoepithelial cells [19].
• Sca-1 and Thy-1 Accelerate Neuron-like Differentiation in Bone Marrow Stromal Cells [20].

Regulatory relationships of Atxn1

• The aim of present study was to determine if intranasally administered IGF-I to SCA1 transgenic mice suppresses toxic effects of ataxin-1 [21].
• Simultaneously, we showed that mutant ataxin-1 promoted interaction between PQBP-1 and RNA polymerase II and enhanced repression of the basal transcription by PQBP-1 [22].

Other interactions of Atxn1

• The cell surface protein Sca-1, which is associated with muscle and blood stem cells, was found on approximately 1/2 of these Bcl-2-positive cells [23].
• A population of cells expressing the endothelial cell marker VEGFR-2/Flk-1, and the progenitor markers c-Kit and Sca-1, were incorporated into tumor tissue [24].
• To determine the effect of enforced expression of Evi1 in vivo, we developed a transgenic mouse model utilizing the murine Sca-1 (Ly-6E.1) promoter [25].
• While the C-kit+ population at this stage is more homogeneous than at any other stage of fetal thymus development, there are still markers (B220, CD5, Tsa, Mac-1, CD4, and Sca-1) that can split this population into other subsets [26].
• Mouse hematopoietic stem-cell antigen Sca-1 is a member of the Ly-6 antigen family [27].
• Our results identify the MEF2-HDAC4 complex as a target for ataxin-1 transcriptional repression activity and suggest a novel pathogenic mechanism whereby ataxin-1 sequesters and inhibits the neuronal survival factor MEF2 [28].

Analytical, diagnostic and therapeutic context of Atxn1

• By using Sca-1 antibody in conjunction with magnetic activated cell sorting (MACS), followed with a flow cytometric cell sorting (FACS) method for CD34 and CD45, we have developed a rapid oval cell isolation protocol with high yields of greater than 90% [29].
• Murine epidermal label-retaining cells isolated by flow cytometry do not express the stem cell markers CD34, Sca-1, or Flk-1 [30].
• Western blotting confirmed elevated Sca-1 protein expression in myocardium 7 days after MI [31].

References