Polyglutamine domain modulates the TBP-TFIIB interaction: Implications for its normal function and neurodegeneration

Emory University, Atlanta, Georgia, United States
Nature Neuroscience (Impact Factor: 16.1). 01/2008; 10(12):1519-28. DOI: 10.1038/nn2011
Source: PubMed


Expansion of the polyglutamine (polyQ) tract in human TATA-box binding protein (TBP) causes the neurodegenerative disease spinocerebellar ataxia 17 (SCA17). It remains unclear how the polyQ tract regulates normal protein function and induces selective neuropathology in SCA17. We generated transgenic mice expressing polyQ-expanded TBP. These mice showed weight loss, progressive neurological symptoms and neurodegeneration before early death. Expanded polyQ tracts reduced TBP dimerization but enhanced the interaction of TBP with the general transcription factor IIB (TFIIB). In SCA17 transgenic mice, the small heat shock protein HSPB1, a potent neuroprotective factor, was downregulated, and TFIIB occupancy of the Hspb1 promoter was decreased. Overexpression of HSPB1 or TFIIB alleviated mutant TBP-induced neuritic defects. These findings implicate the polyQ domain of TBP in transcriptional regulation and provide insight into the molecular pathogenesis of SCA17.

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Available from: Stephen T Warren, Oct 04, 2015
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    • "Mutant TBP accumulates in muscle nuclei and becomes misfolded with age, consistent with its late-onset effect on MyoD function in adult muscles. TBP levels are tightly regulated, since floxed SCA17 KI mice, which express one copy of the normal TBP gene, or are equivalent to heterozygous TBP knockout mice, show the same levels of normal TBP as WT TBP mice, which carry two copies of the normal TBP gene (Friedman et al., 2007, 2008; Yang et al., 2014). Similarly, in SCA17 KI mouse brain and muscle, expressing one copy of mutant TBP can downregulate the level of endogenous normal TBP (Figures 1 and S1). "
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    ABSTRACT: In polyglutamine (polyQ) diseases, large polyQ repeats cause juvenile cases with different symptoms than those of adult-onset patients, who carry smaller expanded polyQ repeats. The mechanisms behind the differential pathology mediated by different polyQ repeat lengths remain unknown. By studying knockin mouse models of spinal cerebellar ataxia-17 (SCA17), we found that a large polyQ (105 glutamines) in the TATA-box-binding protein (TBP) preferentially causes muscle degeneration and reduces the expression of muscle-specific genes. Direct expression of TBP with different polyQ repeats in mouse muscle revealed that muscle degeneration is mediated only by the large polyQ repeats. Different polyQ repeats differentially alter TBP's interaction with neuronal and muscle-specific transcription factors. As a result, the large polyQ repeat decreases the association of MyoD with TBP and DNA promoters. Our findings suggest that specific alterations in protein interactions by large polyQ repeats may account for the unique pathology in juvenile polyQ diseases.
    Cell Reports 09/2015; DOI:10.1016/j.celrep.2015.08.060 · 8.36 Impact Factor
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    • "Consistent with this concept, knockdown of PRMT6 not only suppressed the toxicity of polyglutamineexpanded AR, but it also ameliorated the phenotype of flies overexpressing normal AR, further supporting that PRMT6 contributes to toxicity by enhancing the native function of AR. Moreover , there is evidence that polyglutamine expansion leads to amplification of interaction with native cellular partners, as reported for a variety of polyglutamine proteins, including ataxin-1 (Lim et al., 2008), AR (Nedelsky et al., 2010), and TBP (Friedman et al., 2007). Expanding this idea, we here present evidence that PRMT6 acts as a co-activator of AR whose function is enhanced by polyglutamine expansion. "
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    ABSTRACT: Polyglutamine expansion in androgen receptor (AR) is responsible for spinobulbar muscular atrophy (SBMA) that leads to selective loss of lower motor neurons. Using SBMA as a model, we explored the relationship between protein structure/function and neurodegeneration in polyglutamine diseases. We show here that protein arginine methyltransferase 6 (PRMT6) is a specific co-activator of normal and mutant AR and that the interaction of PRMT6 with AR is significantly enhanced in the AR mutant. AR and PRMT6 interaction occurs through the PRMT6 steroid receptor interaction motif, LXXLL, and the AR activating function 2 surface. AR transactivation requires PRMT6 catalytic activity and involves methylation of arginine residues at Akt consensus site motifs, which is mutually exclusive with serine phosphorylation by Akt. The enhanced interaction of PRMT6 and mutant AR leads to neurodegeneration in cell and fly models of SBMA. These findings demonstrate a direct role of arginine methylation in polyglutamine disease pathogenesis.
    Neuron 01/2015; 85(1):88-100. DOI:10.1016/j.neuron.2014.12.031 · 15.05 Impact Factor
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    • "Previous studies have shed light on the role of repeat expansions in conferring onset of disease, though the exact mechanism by which the polyQ repeat of TBP affects transcription has largely confounded researchers. However, Friedman and colleagues demonstrate the mechanistic role of the polyQ repeats in the transcriptional regulation of TBP [69]. TBP dimerization has previously been shown to prevent unregulated gene expression and modulate its own degradation [70]. "
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    ABSTRACT: Copy Number Variations (CNVs) and Single Nucleotide Polymorphisms (SNPs) have been the major focus of most large-scale comparative genomics studies to date. Here, we discuss a third, largely ignored, type of genetic variation, namely changes in tandem repeat number. Historically, tandem repeats have been designated as non functional "junk" DNA, mostly as a result of their highly unstable nature. With the exception of tandem repeats involved in human neurodegenerative diseases, repeat variation was often believed to be neutral with no phenotypic consequences. Recent studies, however, have shown that as many as 10% to 20% of coding and regulatory sequences in eukaryotes contain an unstable repeat tract. Contrary to initial suggestions, tandem repeat variation can have useful phenotypic consequences. Examples include rapid variation in microbial cell surface, tuning of internal molecular clocks in flies and the dynamic morphological plasticity in mammals. As such, tandem repeats can be useful functional elements that facilitate evolvability and rapid adaptation.
    Genes 12/2012; 3(3):461-80. DOI:10.3390/genes3030461 · 1.15 Impact Factor
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