Opposing effects of polyglutamine expansion on native protein complexes contribute to SCAI

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Nature (Impact Factor: 41.46). 05/2008; 452(7188):713-8. DOI: 10.1038/nature06731
Source: PubMed


Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine-encoding repeat in ataxin 1 (ATXN1). In all known polyglutamine diseases, the glutamine expansion confers toxic functions onto the protein; however, the mechanism by which this occurs remains enigmatic, in light of the fact that the mutant protein apparently maintains interactions with its usual partners. Here we show that the expanded polyglutamine tract differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favours the formation of a particular protein complex containing RBM17, contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism. This model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases.

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Available from: Juan Crespo-Barreto
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    • "Polyglutamine (polyQ) expansion causes at least nine inherited neurodegenerative disorders, including Huntington's disease (HD), spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17, dentatorubral-pallidoluysian atrophy (DRPLA), and spinal bulbar muscular atrophy (SBMA) (Orr and Zoghbi, 2007). Studies of various polyQ disease proteins have shown that expanded polyQ tracts affect the function of the disease proteins, leading to a gain or loss of function (Lim et al., 2008). It is also clear that the function of polyQ proteins can impact disease severity and progression. "
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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.
    Full-text · Article · Sep 2015 · Cell Reports
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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.
    Full-text · Article · Jan 2015 · Neuron
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    • "Zoghbi's group and Orr's group found that mutant Atxn1 must be in its large native complexes to cause neurodegeneration and that its interactions with RBM17 are enhanced at the expense of interactions with CIC (Lam et al, 2006; Lim et al, 2008). Given that RBM17, also called splicing factor 45 (SPF45), is an RNA binding protein involved in splicing and that CIC/Capicua is a Sox2-like highmobility group (HMG) protein involved in transcriptional repression, the shifted balance between splicing and transcription could broadly affect gene and protein expression profiles. "
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    ABSTRACT: Mutant ataxin-1 (Atxn1), which causes spinocerebellar ataxia type 1 (SCA1), binds to and impairs the function of high-mobility group box 1 (HMGB1), a crucial nuclear protein that regulates DNA architectural changes essential for DNA damage repair and transcription. In this study, we established that transgenic or virus vector-mediated complementation with HMGB1 ameliorates motor dysfunction and prolongs lifespan in mutant Atxn1 knock-in (Atxn1-KI) mice. We identified mitochondrial DNA damage repair by HMGB1 as a novel molecular basis for this effect, in addition to the mechanisms already associated with HMGB1 function, such as nuclear DNA damage repair and nuclear transcription. The dysfunction and the improvement of mitochondrial DNA damage repair functions are tightly associated with the exacerbation and rescue, respectively, of symptoms, supporting the involvement of mitochondrial DNA quality control by HMGB1 in SCA1 pathology. Moreover, we show that the rescue of Purkinje cell dendrites and dendritic spines by HMGB1 could be downstream effects. Although extracellular HMGB1 triggers inflammation mediated by Toll-like receptor and receptor for advanced glycation end products, upregulation of intracellular HMGB1 does not induce such side effects. Thus, viral delivery of HMGB1 is a candidate approach by which to modify the disease progression of SCA1 even after the onset.
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