Partial loss of Tip60 slows mid-stage neurodegeneration in a spinocerebellar ataxia type 1 (SCA1) mouse model - PubMed (original) (raw)

. 2011 Jun 1;20(11):2204-12.

doi: 10.1093/hmg/ddr108. Epub 2011 Mar 22.

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Partial loss of Tip60 slows mid-stage neurodegeneration in a spinocerebellar ataxia type 1 (SCA1) mouse model

Kristin M Gehrking et al. Hum Mol Genet. 2011.

Abstract

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. ATXN1 is part of an in vivo complex with retinoid acid receptor-related orphan receptor alpha (Rora) and the acetyltransferase tat-interactive protein 60 kDa (Tip60). ATXN1 and Tip60 interact directly via the ATXN1 and HMG-box protein 1 (AXH) domain of ATXN1. Moreover, the phospho-mimicking Asp amino acid at position 776, previously shown to enhance pathogenesis, increases the ability of ATXN1 to interact with Tip60. Using a genetic approach, the biological relevance of the ATXN1/Tip60 interaction was assessed by crossing ATXN1[82Q] mice with Tip60(+/-)animals. Partial Tip60 loss increased Rora and Rora-mediated gene expression and delayed ATXN1[82]-mediated cerebellar degeneration during mid-stage disease progression. These results suggested a specific, temporal role for Tip60 during disease progression. We also showed that genetic background modulated ATXN1[82Q]-induced phenotypes. Of interest, these latter studies showed that some phenotypes are enhanced on a mixed background while others are suppressed.

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Figures

Figure 1.

Figure 1.

The interaction of ATXN1 with Tip60 requires the AXH domain of ATXN1 and is enhanced by a phospho-mimicking Asp at residue 776. (A) Diagrams of the GST–ATXN1 constructs used to pull-down His-tagged 35S-labeled Tip60. (B) Representative polyacrylamide gel showing the ability of GST–ATXN1 to pull-down His-tagged 35S-labeled Tip60. Upper panel depicts an autoradiograph of 35S-labeled Tip60 pulled down by each GST–ATXN1 construct. Lower panel shows Coomassie stained GST–ATXN1 constructs. (C) Quantification of Tip60 pulled down by GST–ATXN1–fragment V in which the amino acid at position 776 was either a Ser (S776), a phosphorylation resistant Ala (S776A) or phospho-mimicking Asp (S776D).

Figure 2.

Figure 2.

Genetic background affects SCA1 phenotypes in ATXN1[82Q] transgenic mice. (A) Cerebellar molecular layer thickness in aging WT-FVB and FVB;SV-129;C57BL/6 (mix) mice (n = 3–7 mice/genotype/age). (B) Cerebellar molecular layer thickness in aging FVB and FVB;SV-129;C57BL/6 (mix) mice expressing the ATXN1[82Q] transgene (n = 3–7 mice/genotype/age). (C) Motor performance using the accelerating rotarod paradigm in aging FVB;SV-129;C57BL/6 (mix) mice expressing the ATXN1[82Q] transgene (n = 6–12 mice/genotype).

Figure 3.

Figure 3.

Tip60 haploinsufficiency rescues SCA1 cerebellar pathology during the mid-stage of disease. (A) Calbindin immunofluorescence of Purkinje cells in aging WT, ATXN1[82Q] and ATXN1[82Q]:Tip60+/− FVB;SV-129;C57BL/6 (mix) mice. (B) Quantitative analysis of the molecular thickness in aging WT, ATXN1[82Q] and ATXN1[82Q]:Tip60+/− FVB;SV-129;C57BL/6 (mix) mice (n = 3–7 mice/genotype/age). (C) Immunofluorescence of calbindin (red) and VGluT2 (green) in WT, ATXN1[82Q] and ATXN1[82Q]:Tip60+/− FVB;SV-129;C57BL/6 (mix) mice. (D) Quantitative analysis of the climbing fiber extension along Purkinje cell dendrites in aging WT, ATXN1[82Q] and ATXN1[82Q]:Tip60+/− FVB;SV-129;C57BL/6 (mix) mice (n = 3–5 mice/genotype/age).

Figure 4.

Figure 4.

Tip60 haploinsufficiency restoration of Rora levels (n = 3 mice) and Rora-mediated gene expression. (A) Western blot analysis of cerebellar Rora levels in WT, ATXN1[82Q] and ATXN1[82Q]:Tip60+/− FVB;SV-129;C57BL/6 (mix) mice, and in homozygous staggerer (sg/sg) mice at 12 weeks of age. COS cells transfected with Rora cDNA are shown as a positive control. (B) Quantitative PCR of four Rora-mediated genes in WT, ATXN1[82Q] and ATXN1[82Q]:Tip60+/− FVB;SV-129;C57BL/6 (mix) mice at 8 weeks of age. (C) Quantitative PCR of four Rora-mediated genes in WT, ATXN1[82Q] and ATXN1[82Q]Tip60+/− FVB;SV-129;C57BL/6 (mix) mice at 12 weeks of age. (D) Quantitative PCR of four Rora-mediated genes in WT, ATXN1[82Q] and ATXN1[82Q]:Tip60+/− FVB;SV-129;C57BL/6 (mix) mice at 20 weeks of age.

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