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• W2034644012 abstract "The nature of the gain-of-function toxicity found in polyglutamine (polyQ) diseases has been the subject of considerable debate. In this issue of Neuron, Duvick et al. and Nedelsky et al. show that, in two of these diseases, pathology is mediated by normal protein activity. The nature of the gain-of-function toxicity found in polyglutamine (polyQ) diseases has been the subject of considerable debate. In this issue of Neuron, Duvick et al. and Nedelsky et al. show that, in two of these diseases, pathology is mediated by normal protein activity. While many neurodegenerative diseases have been linked to causative proteins, controversy remains. When does a protein contribute to disease through gain of function (GOF), and when is it via loss of function (LOF)? While the interpretation (if not the molecular details) of pathological LOF is generally straightforward, the etiology behind a GOF can be more obscure. A GOF can be a novel property that emerges in a disease-associated protein, or it might result from an enhancement of one or more of the protein's normal functions to toxic levels. Monogenic diseases offer tractable models to examine the nature of a GOF. Two papers in this issue of Neuron seek to do just this by exploring in vivo models of polyglutamine (polyQ) diseases. PolyQ diseases include at least nine neurodegenerative diseases caused by a pathological expansion of CAG repeats in the coding regions of different genes (Orr and Zoghbi, 2007Orr H.T. Zoghbi H.Y. Annu. Rev. Neurosci. 2007; 30: 575-621Crossref PubMed Scopus (1023) Google Scholar). These diseases vary remarkably in the susceptibility of specific brain and spinal cord regions, and together they represent the most common cause of inherited neurodegenerative disease. Direct toxicity of the polyQ stretch has been hypothesized as a common mechanism of polyglutamine diseases. In animal models, a polyQ stretch is sufficient for pathology and aggregation when inserted into a larger protein (Ordway et al., 1997Ordway J.M. Tallaksen-Greene S. Gutekunst C.A. Bernstein E.M. Cearley J.A. Wiener H.W. Dure L.S. Lindsey R. Hersch S.M. Jope R.S. et al.Cell. 1997; 91 (753–63)Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar) or as an independent peptide (Marsh et al., 2000Marsh J.L. Walker H. Theisen H. Zhu Y.Z. Fielder T. Purcell J. Thompson L.M. Hum. Mol. Genet. 2000; 9: 13-25Crossref PubMed Scopus (202) Google Scholar). In this model, the rest of the protein influences only the details of the death and dysfunction. More recently, however, the protein context has been shown to be critical, and in some cases polyQ expansion by itself is not sufficient for disease. For instance, phosphorylation at serine 421 (Humbert et al., 2002Humbert S. Bryson E.A. Cordelieres F.P. Connors N.C. Datta S.R. Finkbeiner S. Greenberg M.E. Saudou F. Dev. Cell. 2002; 2: 831-837Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar) or serines 13 and 16 (Gu et al., 2009Gu X. Greiner E.R. Mishra R. Kodali R. Osmand A. Finkbeiner S. Steffan J.S. Thompson L.M. Wetzel R. Yang X.W. Neuron. 2009; 64: 828-840Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar) of the protein that causes Huntington's disease (HD) abrogates its toxicity. The connection between host protein context and toxicity suggests that the normal function of the protein may be linked to disease. Work by Nedelsky et al., 2010Nedelsky N.B. Pennuto M. Smith R.B. Palazzolo I. Moore J. Nie Z. Neale G. Taylor J.P. Neuron. 2010; 67 (this issue): 936-952Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar on spinal bulbar muscular atrophy (SBMA) in this issue of Neuron suggests just that. SBMA is an X-linked neurodegenerative disease characterized by late-onset muscle weakness and wasting and degeneration of motor neurons in the brainstem and spinal cord (Orr and Zoghbi, 2007Orr H.T. Zoghbi H.Y. Annu. Rev. Neurosci. 2007; 30: 575-621Crossref PubMed Scopus (1023) Google Scholar). The polyQ expansion in SBMA occurs in the androgen receptor (AR), a classic nuclear hormone receptor. This makes SBMA one of the few polyQ diseases in which the function of the host protein is well understood. Nedelsky et al., 2010Nedelsky N.B. Pennuto M. Smith R.B. Palazzolo I. Moore J. Nie Z. Neale G. Taylor J.P. Neuron. 2010; 67 (this issue): 936-952Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar combine existing knowledge about the AR with the power of fly genetics to home in on the source of polyQ toxicity. The authors expressed the human AR with wild-type (12Q) or pathogenic (52Q) glutamine stretches in the adult Drosophila eye or larval salivary glands and motor neurons. In agreement with previous findings, ligand binding and nuclear translocation were necessary to evoke the degenerative phenotype (Katsuno et al., 2002Katsuno M. Adachi H. Kume A. Li M. Nakagomi Y. Niwa H. Sang C. Kobayashi Y. Doyu M. Sobue G. Neuron. 2002; 35: 843-854Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar, Takeyama et al., 2002Takeyama K. Ito S. Yamamoto A. Tanimoto H. Furutani T. Kanuka H. Miura M. Tabata T. Kato S. Neuron. 2002; 35: 855-864Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar). Nuclear translocation alone was insufficient; DNA binding was necessary to cause degeneration. Thus, the first steps of normal AR function are necessary for toxicity. After DNA binding, the AR normally recruits transcriptional coregulators via its AF-1 and AF-2 domains. Preventing normal AF-2 interaction with coregulators rescued the toxicity of mutant AR, suggesting that normal AR-coregulator interactions are necessary for disease. Overexpression or knockdown of a specific coregulator known to bind at the AF-2 domain significantly affected the degenerative phenotype. The authors conclude that the polyQ expansion in the AR mediates toxicity via normal AR interactions. Which interactions are most important for toxicity and their pathogenic mechanism(s) remain unresolved. How might normal interactions cause toxicity? Two observations suggest that toxicity is caused by enhanced AR activity. First, high levels of expression of wild-type AR showed a similar, yet more minor, degenerative phenotype, implying that high levels of normal AR activity, even in the absence of the polyQ expansion, are sufficient to cause degeneration. Second, gene expression profiling showed that expression of the wild-type AR yielded changes similar to those evoked by the mutant AR but to a lesser degree. The similarity in gene expression changes argues that the mild degenerative phenotype seen in flies expressing wild-type AR at high levels is not due to a nonspecific toxicity of overexpression. These data implicate polyQ-mediated enhanced activity of wild-type function as the source of toxicity in SBMA. Independent work in this issue by Duvick et al., 2010Duvick L. Barnes J. Ebner B. Agrawal S. Andresen M. Lim J. Giesler G.J. Zoghbi H.Y. Orr H.T. Neuron. 2010; 67 (this issue): 929-935Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar on the polyQ disease spinocerebellar ataxia type 1 (SCA1) arrives at a similar conclusion. SCA1 is caused by a polyQ-expanded version of the protein ataxin-1 and usually presents in middle age as progressive ataxia, tremor, and dysarthria. Pathology is characterized by marked cerebellar atrophy with Purkinje cell death (Orr and Zoghbi, 2007Orr H.T. Zoghbi H.Y. Annu. Rev. Neurosci. 2007; 30: 575-621Crossref PubMed Scopus (1023) Google Scholar). Protein context is also important in SCA1: phosphorylation at serine 776 of ataxin-1 is necessary for toxicity (Emamian et al., 2003Emamian E.S. Kaytor M.D. Duvick L.A. Zu T. Tousey S.K. Zoghbi H.Y. Clark H.B. Orr H.T. Neuron. 2003; 38: 375-387Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). Mutant ataxin-1 alters the balance of protein-protein interactions between itself and two binding partners, but abolishing phosphorylation at S776 restores the wild-type equilibrium (Lim et al., 2008Lim J. Crespo-Barreto J. Jafar-Nejad P. Bowman A.B. Richman R. Hill D.E. Orr H.T. Zoghbi H.Y. Nature. 2008; 452: 713-718Crossref PubMed Scopus (244) Google Scholar). Intriguingly, mimicking tonic phosphorylation by mutating serine to aspartic acid (S776D) causes wild-type ataxin-1 to interact with these binding partners as if it were polyQ expanded. Duvick et al., 2010Duvick L. Barnes J. Ebner B. Agrawal S. Andresen M. Lim J. Giesler G.J. Zoghbi H.Y. Orr H.T. Neuron. 2010; 67 (this issue): 929-935Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar follow up on this finding to determine if wild-type ataxin-1-S776D can evoke dysfunction and pathology in vivo. They generated transgenic mice with Purkinje cell-specific expression of the wild-type (30Q) or mutant (82Q) ataxin-1 with the S776D mutation. Mice expressing ataxin-1-82Q demonstrated behavioral and histological pathology (Orr and Zoghbi, 2007Orr H.T. Zoghbi H.Y. Annu. Rev. Neurosci. 2007; 30: 575-621Crossref PubMed Scopus (1023) Google Scholar). Furthermore, the ataxin-1-82Q-S776D mice displayed similar pathology despite significantly less transgene expression, reflecting the enhanced toxicity of the mimicked tonic phosphorylation. The surprise came with analysis of the respective wild-type ataxin-1-30Q mouse lines. The ataxin-1-30Q-S776D cohort showed atrophy of Pukinje cell dendritic branches and a retraction of climbing fiber-Purkinje cell synapses, similar to that seen in those mice expressing mutant ataxin-1. The rotarod confirmed a progressive functional deficit. Hence, pathology caused by an expansion of a polyQ stretch was evoked in mice by the same protein with a nonmutant polyQ stretch if the phosphorylation site was mutated. It will be interesting to see if polyQ expansion facilitates phosphorylation at S776 in vivo. If polyQ expansion is not necessary for ataxin-1 toxicity, then the wild-type functions of ataxin-1 alone might be sufficient for disease. Along these lines, mice expressing ataxin-1-30Q with no alteration at S776 showed evidence of pathology. This line has the highest transgene expression level, suggesting that excessive levels of normal ataxin-1 activity represent the GOF caused by polyQ expansion. These two reports demonstrate that normal function of the host protein is crucial to pathogenesis in two distinct polyQ diseases and implicate excessive levels of normal function as the GOF that causes toxicity. Are there any reasons to worry that these model systems might not fully reflect the mechanisms at play in the human conditions? The AR has no direct ortholog in flies, so its interactions are occurring in a nonnative setting. However, the AF-1 and AF-2 domains are conserved in other native nuclear hormone receptors in Drosophila, and the majority of known human nuclear hormone coregulators have orthologs in the fly. Further, data from fly models of SBMA have been broadly consistent with those from mouse models (Katsuno et al., 2002Katsuno M. Adachi H. Kume A. Li M. Nakagomi Y. Niwa H. Sang C. Kobayashi Y. Doyu M. Sobue G. Neuron. 2002; 35: 843-854Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar, Takeyama et al., 2002Takeyama K. Ito S. Yamamoto A. Tanimoto H. Furutani T. Kanuka H. Miura M. Tabata T. Kato S. Neuron. 2002; 35: 855-864Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar). It is also worth considering the increasing evidence of contributions to HD from cell types other than neurons expressing the polyQ expanded protein (Bradford et al., 2009Bradford J. Shin J.Y. Roberts M. Wang C.E. Li X.J. Li S. Proc. Natl. Acad. Sci. USA. 2009; 106: 22480-22485Crossref PubMed Scopus (228) Google Scholar). If similar contributions are made in other polyQ diseases, then they might not be detected in the Drosophila eye or in a mouse with restricted transgene expression. Finally, any developmental contribution to disease, as has been suggested in the case of SCA1 (Orr and Zoghbi, 2007Orr H.T. Zoghbi H.Y. Annu. Rev. Neurosci. 2007; 30: 575-621Crossref PubMed Scopus (1023) Google Scholar), might be difficult to study. Evidence for other causes of toxicity in these diseases exists. In SBMA, for example, patients can experience gynecomastia and hypogonadism, signs of mild androgen insensitivity. On the other hand, frank feminization is not observed, and loss of the AR does not cause neurodegeneration (Orr and Zoghbi, 2007Orr H.T. Zoghbi H.Y. Annu. Rev. Neurosci. 2007; 30: 575-621Crossref PubMed Scopus (1023) Google Scholar), arguing against LOF as the sole cause of toxicity. A mixed GOF and LOF picture for SBMA may best explain patient phenotypes, consistent with in vitro data demonstating both up- and downregulation of target genes by mutant AR expression (Lieberman et al., 2002Lieberman A.P. Harmison G. Strand A.D. Olson J.M. Fischbeck K.H. Hum. Mol. Genet. 2002; 11: 1967-1976Crossref PubMed Scopus (117) Google Scholar). The studies discussed here provide clues as to how polyQ diseases could be explained by a dominant GOF together with a role for LOF (Figure 1). The host protein might adopt one of several conformations that depend on specific posttranslational modifications, e.g., phosphorylation, with different conformations associated with particular functions. In the disease setting, polyQ expansion could stabilize certain conformations of the host protein at the expense of others, disrupting the equilibrium of protein conformations and enhancing the functions associated with certain conformations. PolyQ expansions are also known to place an extra burden on the protein folding machinery (Powers et al., 2009Powers E.T. Morimoto R.I. Dillin A. Kelly J.W. Balch W.E. Annu. Rev. Biochem. 2009; 78: 959-991Crossref PubMed Scopus (780) Google Scholar). Thus, disease might occur through disrupted folding of other metastable proteins, contributing to their LOF. However, it is possible to imagine that the burden on the chaperone system could cause disease by enhancing a normal function of the instigating polyQ protein. A reduced availability of chaperones could shift the distribution of the host protein's conformers toward those that do not require chaperones (Figure 1). The increase in the function that corresponds to that conformer would represent a GOF. Together, these changes might bring about cell dysfunction and eventual death. These findings open the door to new therapeutic opportunities. There are no effective treatments for the polyQ diseases, and the seemingly promising approach of chemical castration for SBMA failed a recent clinical trial (Katsuno et al., 2010Katsuno M. Banno H. Suzuki K. Takeuchi Y. Kawashima M. Yabe I. Sasaki H. Aoki M. Morita M. Nakano I. et al.Lancet Neurol. 2010; 9: 875-884Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). These studies suggest that targeting specific native protein functions may be required for effective treatment. SCA1-like Disease in Mice Expressing Wild-Type Ataxin-1 with a Serine to Aspartic Acid Replacement at Residue 776Duvick et al.NeuronSeptember 23, 2010In BriefGlutamine tract expansion triggers nine neurodegenerative diseases by conferring toxic properties to the mutant protein. In SCA1, phosphorylation of ATXN1 at Ser776 is thought to be key for pathogenesis. Here, we show that replacing Ser776 with a phosphomimicking Asp converted ATXN1 with a wild-type glutamine tract into a pathogenic protein. ATXN1[30Q]-D776-induced disease in Purkinje cells shared most features with disease caused by ATXN1[82Q] having an expanded polyglutamine tract. However, in contrast to disease induced by ATXN1[82Q] that progresses to cell death, ATXN1[30Q]-D776 failed to induce cell death. Full-Text PDF Open ArchiveNative Functions of the Androgen Receptor Are Essential to Pathogenesis in a Drosophila Model of Spinobulbar Muscular AtrophyNedelsky et al.NeuronSeptember 23, 2010In BriefSpinobulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by expansion of a polyglutamine tract in the androgen receptor (AR). This mutation confers toxic function to AR through unknown mechanisms. Mutant AR toxicity requires binding of its hormone ligand, suggesting that pathogenesis involves ligand-induced changes in AR. However, whether toxicity is mediated by native AR function or a novel AR function is unknown. We systematically investigated events downstream of ligand-dependent AR activation in a Drosophila model of SBMA. Full-Text PDF Open Archive" @default.
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• W2034644012 title "PolyQ Disease: Too Many Qs, Too Much Function?" @default.
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