Boat, an AXH domain protein, suppresses the cytotoxicity of mutant ataxin-1

Mizutani, Akifumi; Wang, Lei; Rajan, Harini; Vig, P. J. S.; Alaynick, William A.; Thaler, Joshua P.; Tsai, Chih Cheng

doi:10.1038/sj.emboj.7600785

Cited by 83 publications

(98 citation statements)

References 31 publications

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“…It was also shown that if the proteasome was pharmacologically inhibited, there was an increase in ubiquitylated Sens/Gfi-1, suggesting that ataxin-1 enhanced the degradation of Sens/Gfi-1 via the ubiquitin proteasome system. This is interesting in light of the second report in which the level of Boat (Brother of ataxin-1) was reduced in the Purkinje cells of SCA1 transgenic mice (Mizutani et al 2005). It was not demonstrated that this was due to enhanced proteasomal degradation, but it seems probable in light of the Sens/Gfi-1 result.…”

Section: Sca1: Corepressors and Remodeling At Sites Of Transcriptionmentioning

confidence: 95%

“…The roles of regions outside the polyglutamine stretch in mediating mutant ataxin-1 toxicity have been established; however, two recent reports have underscored the importance of ataxin-1's AXH (ataxin-1 and HMGbox protein 1) domain in mediating transcriptional regulatory events and neurodegeneration (Mizutani et al 2005;Tsuda et al 2005). Overexpression of mutant ataxin-1 resulted in a reduction of the transcription factor Senseless (Sens)/Gfi-1 in Purkinje cells.…”

Section: Sca1: Corepressors and Remodeling At Sites Of Transcriptionmentioning

confidence: 99%

“…It was not demonstrated that this was due to enhanced proteasomal degradation, but it seems probable in light of the Sens/Gfi-1 result. Boat also contains an AXH domain important for Boat's interaction with SMRT and ability to repress transcription (Mizutani et al 2005). …”

Section: Sca1: Corepressors and Remodeling At Sites Of Transcriptionmentioning

confidence: 99%

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Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle

Riley¹,

Orr²

2006

Genes Dev.

132

106

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The polyglutamine disorders are a class of nine neurodegenerative disorders that are inherited gain-of-function diseases caused by expansion of a translated CAG repeat. Even though the disease-causing proteins are widely expressed, specific collections of neurons are more susceptible in each disease, resulting in characteristic patterns of pathology and clinical symptoms. One hypothesis poses that altered protein function is fundamental to pathogenesis, with protein context of the expanded polyglutamine having key roles in diseasespecific processes. This review will focus on the role of the disease-causing polyglutamine proteins in gene transcription and the extent to which the mutant proteins induce disruption of transcription.One of the intriguing developments in human genetics is the identification of a mutational mechanism apparently unique to the human genome, the expansion of unstable nucleotide repeats (Gatchel and Zoghbi 2005). Depending on the genetic context of the unstable repeat, the pathogenic mechanism underlying the disorder can be either a loss-of-function or gain-of-function mutation operating at either the RNA or protein level. A subclass of the unstable repeat disorders is caused by the expansion of an unstable CAG trinucleotide repeat located within the protein encoding region such that the repeat is translated into a stretch of glutamine residues; i.e., the polyglutamine diseases. Although rare as a group, the polyglutamine disorders represent the most common form of inherited neurodegenerative disease. At present, nine disorders make up this class of neurodegenerative disease (Table 1). Initially, it was argued that the genetic similarities among these disorders strongly supported the hypothesis that these disorders shared a common mechanism of pathogenesis entirely dependent on the toxic properties of the polyglutamine tract. This typically centered on the enhanced ability of polyglutamine peptides to form intranuclear aggregates/inclusions (Ross and Poirer 2004). The presence of these aggregates/ inclusions within the nuclei of affected neurons focused attention on the nucleus as the subcellular site important in pathogenesis. After much study, the concept of large aggregates/inclusions of mutant polyglutamine as the pathogenic species has become suspect (Arrasate et al. 2004). However, for many of the polyglutamine disorders, understanding events in the nucleus still remains crucial for comprehending pathogenesis.Expansion of the polyglutamine tract is the trigger for pathogenesis. Yet, it likely does so by acting in concert with the other amino acids of the "host" protein (Orr 2001). This point is nicely illustrated by studies on SCA1 and AR/SBMA. In the case of SCA1, replacing single amino acids in ataxin-1 outside of its polyglutamine tract dramatically reduced the ability of mutant ataxin-1 (ataxin-1[82Q]) to cause disease in vivo (Klement et al. 1998;Emamian et al. 2003). In SBMA, androgen binding to the ligand-binding region in AR is critical for pathogenesis (Katsuno et al. 2002(K...

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Section: Sca1: Corepressors and Remodeling At Sites Of Transcriptionmentioning

confidence: 95%

Section: Sca1: Corepressors and Remodeling At Sites Of Transcriptionmentioning

confidence: 99%

See 1 more Smart Citation

Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle

Riley¹,

Orr²

2006

Genes Dev.

132

106

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“…A self-association region of the non-expanded protein was mapped in the centre of the protein and identified to overlap the only certified globular domain of the otherwise PeerJ PrePrints | http://dx.doi.org/10.7287/peerj.preprints.259v1 | CC-BY 4.0 Open Access | received: , published: 27 Feb 2014 mostly unstructured protein, the AXH domain that spans residues 562-689 (SMART SM00536) (Burright et al, 1997;de Chiara et al, 2003). This motif is functionally very important as it is involved in transcriptional regulation as well as in the RNA-binding activity of ataxin-1 (Matilla et al, 1997;Okazawa et al 2002;Tsai et al, 2004;de Chiara et al, 2003;de Chiara et al, 2005;Mizutani et al, 2005;Tsuda et al 2005;Lam et al, 2006;Serra et al, 2006;Goold et al, 2007;Lee et al 2011). AXH is also necessary and sufficient for the majority of the known interactions of ataxin-1 with other proteins, most of which are transcriptional regulators (Tsai et al, 2004;Tsuda et al 2005;Lam et al, 2006;Goold et al, 2007;Serra et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Mapping the self-association domains of ataxin-1: Identification of novel non overlapping motifs

Menon

Soong

Chiara

et al. 2014

Preprint

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The neurodegenerative spinocerebellar ataxia type 1 (SCA1) is caused by aggregation and misfolding of the ataxin-1 protein. While the pathology correlates with mutations that lead to expansion of a polyglutamine tract in the protein, other regions contribute to the aggregation process as also non-expanded ataxin-1 is intrinsically aggregation-prone and forms nuclear foci in cell. Here, we have used a combined approach based on FRET analysis, confocal microscopy and in vitro techniques to map aggregation-prone regions other than polyglutamine and to establish the importance of dimerization in self-association/foci formation. Identification of aggregation-prone regions other than polyglutamine could greatly help the development of SCA1 treatment more specific than that based on targeting the low complexity polyglutamine region.PeerJ PrePrints | http://dx.doi.org/10.7287/peerj.preprints.259v1 | CC-BY 4.0

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“…Second to RNA binding, the AXH domain contains a cluster of charged surface residues that allows for another secondary binding surface. This leads to the several protein-protein interactions through the ataxin-1 AXH domain, namely a paralog of ataxin-1, brother of ataxin-1 (BOAT), which also contains a AXH domain, the SMRT/SMRTER and Capicua proteins [94]. These interactions, along with interactions between several transcriptional factors, give ataxin-1 its transcriptional repression activity [90,91,93].…”

Section: Wild-type and Mutant Proteinmentioning

confidence: 99%

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

McIntosh¹,

Htut²,

Fletcher³

et al. 2017

J Genet Syndr Gene Ther

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Spinocerebellar ataxias are a large group of heterogeneous diseases that all involve selective neuronal degeneration and accompanied cerebellar ataxia. These diseases can be further broken down into discrete groups according to their underlying molecular genetic cause. The most common are the polyglutamine ataxias, of which there are six; Spinocerebellar ataxia type 1, 2, 3, 6, 7 and 17. These diseases are characterised by a pathological expanded cytosine-adenine-guanine (CAG) repeat sequence, in the protein coding region of a given gene. Common clinical features include lack of coordination and gait ataxia, speech and swallowing difficulties, as well as impaired hand and motor functions. The polyglutamine spinocerebellar ataxias are typically late onset diseases that are progressive in nature and often lead to premature death, for which there is currently no known cure or effective treatment strategy. Although caused by the same molecular mechanism, the causative gene and associated protein differ for each disease. The exact mechanism by which disease pathogenesis is caused remains elusive. However, the variable (CAG) n repeats are codons that may be translated to an expanded glutamine tract, leading to conformational changes in the protein, giving it a toxic gain of function. Several pathogenic pathways have been implicated in polyglutamine spinocerebellar ataxia diseases, such as the hallmark feature of neuronal nuclear inclusions, protein misfolding and aggregation, as well as transcriptional dysregulation. These pathways are attractive avenues for potential therapeutic interventions, as the potential to treat more than one disease exists. Research is ongoing, and several promising therapies are currently underway in an attempt to provide relief for this devastating class of diseases.. However, mutations can arise de novo, through errors in DNA replication such that two genetically healthy parents can give rise to an affected child.There are currently six characterised polyQ SCAs (1, 2, 3, 6, 7 and 17) (Table 1), and together with three other diseases, namely Huntington's disease, spinal and bulbar muscular atrophy and dentatorubropallidoluysian atrophy (DRPLA), form a larger category of polyQ diseases [7][8][9][10]. Th ere is little relief for individuals suffering from polyQ SCA disorders, with symptomatic treatments the only available option. Long term pharmacological treatment, although admirable, tends to fall short in an effective management strategy, as unwanted complications and low drug efficacy still exist. In addition, none of these diseases have any treatments that slow the progression of the disease; leaving affected individuals with the daunting reality that time may be a severe limiting factor. Several experimental approaches are currently being assessed to overcome these difficulties. This review will focus on the clinical and molecular features of polyQ SCA diseases (which will be referred to as SCA diseases), as well as highlight several promising and emerging therapeutic strategies...

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Boat, an AXH domain protein, suppresses the cytotoxicity of mutant ataxin-1

Cited by 83 publications

References 31 publications

Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle

Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle

Mapping the self-association domains of ataxin-1: Identification of novel non overlapping motifs

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

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