Canadian Association of Neurosciences Review: Polyglutamine Expansion Neurodegenerative Diseases

Truant, Ray; Raymond, Lynn A.; Xia, Jianrun; Pinchev, Deborah; Burtnik, Anjee; Atwal, Randy Singh

doi:10.1017/s031716710000514x

Cited by 11 publications

(12 citation statements)

References 190 publications

(212 reference statements)

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“…Animal models of HD require very long polyglutamine tracts to elicit any obvious phenotypic changes; however, using our huntingtin exon1 FRET sensor, we have been able to detect a conformational switch between 32 and 37 glutamine repeats in live cells. Huntingtin is one of nine polyglutamine expansion disease proteins, where the biological role of normal polyglutamine tracts in these proteins is not understood (28). In transcription factors such as the Sp-family, CREB, and TLE, glutamine-rich domains are thought to mediate protein-protein interactions and/or dimerization (6)(7)(8).…”

Section: Measuring the Conformation Of The Amino Terminus Within Thementioning

confidence: 99%

Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin

Caron

Desmond

Xia

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion within the huntingtin gene that encodes a polymorphic glutamine tract at the amino terminus of the huntingtin protein. HD is one of nine polyglutamine expansion diseases. The clinical threshold of polyglutamine expansion for HD is near 37 repeats, but the mechanism of this pathogenic length is poorly understood. Using Förster resonance energy transfer, we describe an intramolecular proximity between the N17 domain and the downstream polyproline region that flanks the polyglutamine tract of huntingtin. Our data support the hypothesis that the polyglutamine tract can act as a flexible domain, allowing the flanking domains to come into close spatial proximity. This flexibility is impaired with expanded polyglutamine tracts, and we can detect changes in huntingtin conformation at the pathogenic threshold for HD. Altering the structure of N17, either via phosphomimicry or with small molecules, also affects the proximity between the flanking domains. The structural capacity of N17 to fold back toward distal regions within huntingtin requires an interacting protein, protein kinase C and casein kinase 2 substrate in neurons 1 (PACSIN1). This protein has the ability to bind both N17 and the polyproline region, stabilizing the interaction between these two domains. We also developed an antibody-based FRET assay that can detect conformational changes within endogenous huntingtin in wild-type versus HD fibroblasts. Therefore, we hypothesize that wild-type length polyglutamine tracts within huntingtin can form a flexible domain that is essential for proper functional intramolecular proximity, conformations, and dynamics.polyglutamine diseases | conformational switching | FLIM-FRET | neurodegeneration | fluorescence lifetime imaging microscopy H untington disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat within the huntingtin (HTT) gene (1). The pathogenic threshold of CAG expansion is ∼37 repeats, with increased repeats leading to an earlier age-onset of HD (2-4). This CAG mutation results in an expanded polyglutamine tract in the amino terminus of the gene's protein product, huntingtin (1). To date, no phenotypes at the level of huntingtin molecular biology or animal models can be attributed to polyglutamine lengths near the human pathogenic disease threshold (5).Polyglutamine or glutamine-rich domains are also found in transcription factors such as the Sp-family and cAMP response element-binding protein (CREB) and are defined as proteinprotein interaction motifs used to scaffold and regulate transcription by RNA polymerase II (6, 7). In the transducin-like enhancer of split (TLE) corepressor proteins, the glutamine-rich domains are thought to allow dimerization (8). However, the role of polyglutamine in proteins such as huntingtin may be distinct from that of a protein-protein interaction or dimerization domain.The polyglutamine tract of huntingtin is flanked on...

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Section: Measuring the Conformation Of The Amino Terminus Within Thementioning

confidence: 99%

Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin

Caron

Desmond

Xia

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

129

150

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“…Of note, some knowledge was gained by exploring the physiological function of paralogous proteins identified for several disease proteins. Regarding the family of polyglutamine disorders, which includes Huntington’s disease, spinobulbar muscular atrophy, dentatorubral pallidoluysian atrophy, and spinocerebellar ataxia (SCA) type 1, 2, 3, 6, 7 & 17 [1], [2], [3], [4], a gene duplication of ataxin-1-like (ATXN1L)/Brother of ataxin-1 (Boat), the respective paralog of the disease-causing protein ataxin-1 (ATXN1), ameliorated the observed neurotoxicity in a SCA1 mouse model, indicating overlapping functionality between paralog and disease protein [5].…”

Section: Introductionmentioning

confidence: 99%

Ataxin-2-Like Is a Regulator of Stress Granules and Processing Bodies

et al. 2012

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Paralogs for several proteins implicated in neurodegenerative disorders have been identified and explored to further facilitate the identification of molecular mechanisms contributing to disease pathogenesis. For the disease-causing protein in spinocerebellar ataxia type 2, ataxin-2, a paralog of unknown function, termed ataxin-2-like, has been described. We discovered that ataxin-2-like associates with known interaction partners of ataxin-2, the RNA helicase DDX6 and the poly(A)-binding protein, and with ataxin-2 itself. Furthermore, we found that ataxin-2-like is a component of stress granules. Interestingly, sole ataxin-2-like overexpression led to the induction of stress granules, while a reduction of stress granules was detected in case of a low ataxin-2-like level. Finally, we observed that overexpression of ataxin-2-like as well as its reduction has an impact on the presence of microscopically visible processing bodies. Thus, our results imply a functional overlap between ataxin-2-like and ataxin-2, and further indicate a role for ataxin-2-like in the regulation of stress granules and processing bodies.

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“…Others include Huntington’s disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and six spinocerebellar ataxias [SCA1, SCA2, SCA3 (Machado-Joseph disease), SCA-6, SCA-7, SCA-17 (Truant et al, 2006; Orr and Zoghbi, 2007; La Spada and Taylor, 2010)]. Except for SBMA, which is X-linked, these disorders are inherited in an autosomal-dominant fashion.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms Mediating Spinal and Bulbar Muscular Atrophy: Investigations into Polyglutamine-Expanded Androgen Receptor Function and Dysfunction

Beitel¹,

Alvarado²,

Mokhtar³

et al. 2013

Front. Neurol.

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Spinal and bulbar muscular atrophy (SBMA, Kennedy’s disease), a late-onset neuromuscular disorder, is caused by expansion of the polymorphic polyglutamine tract in the androgen receptor (AR). The AR is a ligand-activated transcription factor, but plays roles in other cellular pathways. In SBMA, selective motor neuron degeneration occurs in the brainstem and spinal cord, thus the causes of neuronal dysfunction have been studied. However, pathogenic pathways in muscles may also be involved. Cultured cells, fly and mouse models are used to study the molecular mechanisms leading to SBMA. Both the structure of the polyglutamine-expanded AR (polyQ AR) and its interactions with other proteins are altered relative to the normal AR. The ligand-dependent translocation of the polyQ AR to the nucleus appears to be critical, as are interdomain interactions. The polyQ AR, or fragments thereof, can form nuclear inclusions, but their pathogenic or protective nature is unclear. Other data suggests soluble polyQ AR oligomers can be harmful. Post-translational modifications such as phosphorylation, acetylation, and ubiquitination influence AR function and modulate the deleterious effects of the polyQ AR. Transcriptional dysregulation is highly likely to be a factor in SBMA; deregulation of non-genomic AR signaling may also be involved. Studies on polyQ AR-protein degradation suggest inhibition of the ubiquitin proteasome system and changes to autophagic pathways may be relevant. Mitochondrial function and axonal transport may also be affected by the polyQ AR. Androgens, acting through the AR, can be neurotrophic and are important in muscle development; hence both loss of normal AR functions and gain of novel harmful functions by the polyQ AR can contribute to neurodegeneration and muscular atrophy. Thus investigations into polyQ AR function have shown that multiple complex mechanisms lead to the initiation and progression of SBMA.

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Canadian Association of Neurosciences Review: Polyglutamine Expansion Neurodegenerative Diseases

Cited by 11 publications

References 190 publications

Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin

Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin

Ataxin-2-Like Is a Regulator of Stress Granules and Processing Bodies

Mechanisms Mediating Spinal and Bulbar Muscular Atrophy: Investigations into Polyglutamine-Expanded Androgen Receptor Function and Dysfunction

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