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

Institute of Human Genetics and Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
Human Molecular Genetics (Impact Factor: 6.39). 03/2011; 20(11):2204-12. DOI: 10.1093/hmg/ddr108
Source: PubMed


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.

Download full-text


Available from: PubMed Central · License: CC BY-NC
  • Source
    • "Unfortunately, while Tip60 mRNA expression levels were reduced by approximately 50% in eWAT of Tip60+/− animals, Tip60 protein expression levels were not significantly different between the two genotypes (Fig. 5). This phenomenon has previously been reported in other tissues including B cells [11], cerebellum [21], as well as heart, liver, brain, skeletal muscle and kidney [16]. Taken together these findings suggest that the intact Tip60 allele in heterozygous animals compensates for the ablated Tip60 allele in order to maintain normal cellular function. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adipose tissue is a key regulator of energy homestasis. The amount of adipose tissue is largely determined by adipocyte differentiation (adipogenesis), a process that is regulated by the concerted actions of multiple transcription factors and cofactors. Based on in vitro studies in murine 3T3-L1 preadipocytes and human primary preadipocytes, the transcriptional cofactor and acetyltransferase Tip60 was recently identified as an essential adipogenic factor. We therefore investigated the role of Tip60 on adipocyte differentiation and function, and possible consequences on energy homeostasis, in vivo. Because homozygous inactivation results in early embryonic lethality, Tip60+/- mice were used. Heterozygous inactivation of Tip60 had no effect on body weight, despite slightly higher food intake by Tip60+/- mice. No major effects of heterozygous inactivation of Tip60 were observed on adipose tissue and liver, and Tip60+/- displayed normal glucose tolerance, both on a low fat and a high fat diet. While Tip60 mRNA was reduced to 50% in adipose tissue, the protein levels were unaltered, suggesting compensation by the intact allele. These findings indicate that the in vivo role of Tip60 in adipocyte differentiation and function cannot be properly addressed in Tip60+/- mice, but requires the generation of adipose tissue-specific knock out animals or specific knock-in mice.
    Full-text · Article · May 2014 · PLoS ONE
  • Source
    • "However, overexpression of non-expanded ATX1 (30Q) in flies and mice causes phenotypes similar to those caused by overexpression of drosophila ATX1 which lacks the polyQ tract but different from those observed for polyQ peptides [10], [11] strongly suggesting the presence of at least a second aggregation hotspot. This has been identified in the AXH domain (SMART SM00536) [12], a motif responsible for transcriptional repression and RNA-binding activity of ATX1 [5], [11], [13], [14], [15], [16], [17], [18]. The AXH domain is also necessary and sufficient for the majority of the known ATX1 interactions with other proteins, most of which are transcriptional regulators (SMRT, Gfi-1, CIC, Sp1 and Tip60) [11], [13], [14], [15], [16]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A main challenge for structural biologists is to understand the mechanisms that discriminate between molecular interactions and determine function. Here, we show how partner recognition of the AXH domain of the transcriptional co-regulator ataxin-1 is fine-tuned by a subtle balance between self- and hetero-associations. Ataxin-1 is the protein responsible for the hereditary spinocerebellar ataxia type 1, a disease linked to protein aggregation and transcriptional dysregulation. Expansion of a polyglutamine tract is essential for ataxin-1 aggregation, but the sequence-wise distant AXH domain plays an important aggravating role in the process. The AXH domain is also a key element for non-aberrant function as it intervenes in interactions with multiple protein partners. Previous data have shown that AXH is dimeric in solution and forms a dimer of dimers when crystallized. By solving the structure of a complex of AXH with a peptide from the interacting transcriptional repressor CIC, we show that the dimer interface of AXH is displaced by the new interaction and that, when blocked by the CIC peptide AXH aggregation and misfolding are impaired. This is a unique example in which palindromic self- and hetero-interactions within a sequence with chameleon properties discriminate the partner. We propose a drug design strategy for the treatment of SCA1 that is based on the information gained from the AXH/CIC complex.
    Full-text · Article · Oct 2013 · PLoS ONE
  • Source
    • "CAG trinucleotide extensions of 41-81 repeats within the coding region of ATXN1 are responsible for the autosomal dominant spinocerebellar ataxia 1 (SCA1 [MIM 164400]), a neurodegenerative disorder with progressive cerebellar degeneration. ATXN1 is also proposed to function as a regulator of gene expression [42]. Interestingly, Atxn1 homozygous knockout mice were shown to share aberrations with a knock-in mouse model of SCA1 that contained the polyglutamine extension [43,44]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Interstitial deletions of the short arm of chromosome 6 are rare and have been associated with developmental delay, hypotonia, congenital anomalies, and dysmorphic features. We used array comparative genomic hybridization in a South Carolina Autism Project (SCAP) cohort of 97 subjects with autism spectrum disorders (ASDs) and identified an ~ 5.4 Mb deletion on chromosome 6p22.3-p23 in a 15-year-old patient with intellectual disability and ASDs. Subsequent database queries revealed five additional individuals with overlapping submicroscopic deletions and presenting with developmental and speech delay, seizures, behavioral abnormalities, heart defects, and dysmorphic features. The deletion found in the SCAP patient harbors ATXN1, DTNBP1, JARID2, and NHLRC1 that we propose may be responsible for ASDs and developmental delay.
    Full-text · Article · Apr 2012 · Molecular Cytogenetics
Show more