Spinocerebellar ataxia 7 (SCA7)

Lèbre, Anne Sophie; Brice, Alexis

doi:10.1159/000072850

Cited by 58 publications

(56 citation statements)

References 55 publications

(103 reference statements)

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“…pinocerebellar ataxia type 7 (SCA7) is one of nine polyglutamine [poly(Q)] expansion diseases associated with progressive neurodegeneration (1)(2)(3). SCA7 is caused by poly(Q) expansions within the N-terminal (NT) region of ATXN7.…”

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confidence: 99%

Poly(Q) Expansions in ATXN7 Affect Solubility but Not Activity of the SAGA Deubiquitinating Module

Lan

Koutelou

Schibler

et al. 2015

Molecular and Cellular Biology

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c Spinocerebellar ataxia type 7 (SCA7) is a debilitating neurodegenerative disease caused by expansion of a polyglutamine [poly(Q)] tract in ATXN7, a subunit of the deubiquitinase (DUB) module (DUBm) in the SAGA complex. The effects of ATXN7-poly(Q) on DUB activity are not known. To address this important question, we reconstituted the DUBm in vitro with either wild-type ATXN7 or a pathogenic form, ATXN7-92Q NT, with 92 Q residues at the N terminus (NT). We found that both forms of ATXN7 greatly enhance DUB activity but that ATXN7-92Q NT is largely insoluble unless it is incorporated into the DUBm. Cooverexpression of DUBm components in human astrocytes also promoted the solubility of ATXN7-92Q, inhibiting its aggregation into nuclear inclusions that sequester DUBm components, leading to global increases in ubiquitinated H2B (H2Bub) levels. Global H2Bub levels were also increased in the cerebellums of mice in a SCA7 mouse model. Our findings indicate that although ATXN7 poly(Q) expansions do not change the enzymatic activity of the DUBm, they likely contribute to SCA7 by initiating aggregates that sequester the DUBm away from its substrates.

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confidence: 99%

Poly(Q) Expansions in ATXN7 Affect Solubility but Not Activity of the SAGA Deubiquitinating Module

Lan

Koutelou

Schibler

et al. 2015

Molecular and Cellular Biology

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“…SCA7 is a member of a family of neurodegenerative diseases in which a CAG DNA triplet repeat expansion results in polyglutamine expansion in the gene product (2). Other members of this polyglutamine expansion disease family include Huntington disease, spinobulbar muscle atrophy, dentatorubral pallidoluysian atrophy, and spinocerebellar ataxia types 1, 2, 3, 6, and 17 (3,4).…”

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confidence: 99%

Ataxin-7 Can Export from the Nucleus via a Conserved Exportin-dependent Signal

Taylor

Grote

Xia

et al. 2006

Journal of Biological Chemistry

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Spinocerebellar ataxia type 7 is a progressive neurodegenerative disorder caused by a CAG DNA triplet repeat expansion leading to an expanded polyglutamine tract in the ataxin-7 protein. Ataxin-7 appears to be a transcription factor and a component of the STAGA transcription coactivator complex. Here, using live cell imaging and inverted fluorescence recovery after photobleaching, we demonstrate that ataxin-7 has the ability to export from the nucleus via the CRM-1/exportin pathway and that ataxin-7 contains a classic leucine-type nuclear export signal (NES). We have precisely defined the location of this NES in ataxin-7 and found it to be fully conserved in all vertebrate species. Polyglutamine expansion was seen to reduce the nuclear export rate of mutant ataxin-7 relative to wildtype ataxin-7. Subtle point mutation of the NES in polyglutamine expanded ataxin-7 increased toxicity in primary cerebellar neurons in a polyglutamine length-dependent manner in the context of fulllength ataxin-7. Our results add ataxin-7 to a growing list of polyglutamine disease proteins that are capable of nuclear shuttling, and we define an activity of ataxin-7 in the STAGA complex of trafficking between the nucleus and cytoplasm. Spinocerebellar ataxia type 7 (SCA7)4 is a dominantly inherited neurodegenerative disorder characterized by loss of neurons in the cerebellum, brain stem, and retina (1). SCA7 is a member of a family of neurodegenerative diseases in which a CAG DNA triplet repeat expansion results in polyglutamine expansion in the gene product (2). Other members of this polyglutamine expansion disease family include Huntington disease, spinobulbar muscle atrophy, dentatorubral pallidoluysian atrophy, and spinocerebellar ataxia types 1, 2, 3, 6, and 17 (3, 4). One unique feature of SCA7 is the loss of photoreceptor neurons in the retina leading to cone-rod dystrophy (5). The mutant ataxin-7 protein can have polyglutamine repeats from 38 to 300 residues in length (6). Ataxin-7 subcellular localization has been seen to be primarily nuclear with nuclear import signals (NLSs) defined in both the central (7), and carboxyl-terminal regions of the protein (8). Within the nucleus, ataxin-7 is known to be a subunit of the mammalian GCN5 histone acetyltransferase STAGA transcription coactivator complex (9). Ataxin-7 directly binds GCN5, and mutant ataxin-7 can inhibit the histone acetyltransferase activity of STAGA (10). Although the precise biological function of ataxin-7 is unknown, mutant ataxin-7 is known to interfere with Crx-dependent transcription of retinal photoreceptor-specific genes (11, 12). Ataxin-7 interacts with TFTC/STAGA protein subunits through a central evolutionarily conserved block of residues that have defined an ataxin-7 homology family in species ranging from human to yeast (9). In Saccharomyces cerevisiae, the yeast ataxin-7 homolog, Sgf73, is a member of the SAGA and SLIK histone acetyltransferase complexes (13). Ataxin-7 and the Crx homeodomain transcription factor interact via glutamine regions in each p...

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“…Spinocerebellar ataxia 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by cerebellar ataxia associated with progressive macular dystrophy [1,2]. SCA7 is generally considered to be caused by expansion of a CAG repeat encoding polyglutamine (polyQ) tract in the protein ataxin-7 (Atx7) [3].…”

Section: Introductionmentioning

confidence: 99%

“…The intranuclear inclusions found in human SCA7 brain contain many other proteins, including transcriptional regulators, ubiquitin/proteasome pathway components, cell death associated proteins, and chaperones and their partners [1]. The function of all these proteins can possibly be influenced by polyQ expansion of Atx7.…”

Section: Introductionmentioning

confidence: 99%

Structural basis for recognition of the third SH3 domain of full‐length R85 (R85FL)/ponsin by ataxin‐7

Jiang

Zhou

et al. 2013

FEBS Letters

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Edited by Berend WieringaKeywords: Ataxin-7 Proline-rich region R85FL/ponsin SH3 domain Polyglutamine Inclusion body a b s t r a c t Ataxin-7 (Atx7) is a component of the nuclear transcription co-activator complex; its polyglutamine (polyQ) expansion may cause nuclear accumulation and recruit numerous proteins to the intranuclear inclusion bodies. Full-length R85 (R85FL) is such a protein sequestered by polyQ-expanded Atx7. Here, we report that Atx7 specifically interacts with the third SH3 domain (SH3C) of R85FL through its second portion of proline-rich region (PRR). NMR structural analysis of the SH3C domain and its complex with PRR revealed that SH3C contains a large negatively charged surface for binding with the RRTR motif of Atx7. Microscopy imaging demonstrated that sequestration of R85FL by the polyQ-expanded Atx7 in cell is mediated by this specific SH3C-PRR interaction, which is implicated in the pathogenesis of spinocerebellar ataxia 7. Structured summary of protein interactions:Atx7 PP2 and SH3C bind by isothermal titration calorimetry (View Interaction: 1,2,3,4,5,6,7,8,9,10,11,12) Atx7 binds to SH3C by pull down (View interaction) Atx7 100Q and SH3C colocalize by fluorescence microscopy (View interaction) SH3C and Atx7 bind by nuclear magnetic resonance (View interaction)

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Spinocerebellar ataxia 7 (SCA7)

Cited by 58 publications

References 55 publications

Poly(Q) Expansions in ATXN7 Affect Solubility but Not Activity of the SAGA Deubiquitinating Module

Poly(Q) Expansions in ATXN7 Affect Solubility but Not Activity of the SAGA Deubiquitinating Module

Ataxin-7 Can Export from the Nucleus via a Conserved Exportin-dependent Signal

Structural basis for recognition of the third SH3 domain of full‐length R85 (R85FL)/ponsin by ataxin‐7

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