Insights into the molecular basis of polyglutamine neurodegeneration from studies of a spinocerebellar ataxia type 7 mouse model

Grote, Sara K.; Spada, Albert R. La

doi:10.1159/000072851

Cited by 12 publications

(9 citation statements)

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“…The presence of aggregates was shown to reduce the concentration of diffuse polyQ-expanded Htt and an increased neuronal survival [53]. It has been suggested that monomeric and oligomeric polyQ-expanded Htt protein exhibit cellular toxicity while formation of larger aggregates provides (at least temporary) protection from these toxic effects [52, 54]. These larger aggregates might eventually exhibit secondary pathogenic effects such as physically blocking vesicle or mitochondrial trafficking in the cell.…”

Section: Discussionmentioning

confidence: 99%

The dynamics of early-state transcriptional changes and aggregate formation in a Huntington’s disease cell model

et al. 2017

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BackgroundHuntington’s disease (HD) is a fatal neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene. Proteolytic cleavage of mutant huntingtin (Htt) protein with an expanded polyglutamine (polyQ) stretch results in production of Htt fragments that aggregate and induce impaired ubiquitin proteasome, mitochondrial functioning and transcriptional dysregulation. To understand the time-resolved relationship between aggregate formation and transcriptional changes at early disease stages, we performed temporal transcriptome profiling and quantification of aggregate formation in living cells in an inducible HD cell model.ResultsRat pheochromocytoma (PC12) cells containing a stably integrated, doxycycline-inducible, eGFP-tagged N-terminal human Htt fragment with an expanded polyQ domain were used to analyse gene expression changes at different stages of mutant Htt aggregation. At earliest time points after doxycycline induction no detectable aggregates and few changes in gene expression were observed. Aggregates started to appear at intermediate time points. Aggregate formation and subsequent enlargement of aggregates coincided with a rapid increase in the number of differentially expressed (DE) genes. The increase in number of large aggregates coincided with a decrease in the number of smaller aggregates whereas the transcription profile reverted towards the profile observed before mutant Htt induction. Cluster-based analysis of the 2,176 differentially expressed genes revealed fourteen distinct clusters responding differently over time. Functional enrichment analysis of the two major gene clusters revealed that genes in the up-regulated cluster were mainly involved in metabolic (antioxidant activity and cellular ketone metabolic processes) and genes in the down-regulated cluster in developmental processes, respectively. Promoter-based analysis of the identified gene clusters resulted in identification of a transcription factor network of which several previously have been linked to HD.ConclusionsWe demonstrate a time-resolved relationship between Htt aggregation and changes in the transcriptional profile. We identified two major gene clusters showing involvement of (i) mitochondrial dysfunction and (ii) developmental processes implying cellular homeostasis defects. We identified novel and known HD-linked transcription factors and show their interaction with known and predicted regulatory proteins. Our data provide a novel resource for hypothesis building on the role of transcriptional key regulators in early stages of HD and possibly other polyQ-dependent diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3745-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The dynamics of early-state transcriptional changes and aggregate formation in a Huntington’s disease cell model

et al. 2017

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Section: Discussionmentioning

confidence: 99%

“…The Sca7 gene that encodes Ataxin-7 is subject to polyglutamine (poly-Q) expansions in humans, giving rise to spinocerebellar ataxia (15). Mouse models of poly-Q expansions of Sca7 exhibit many phenotypes similar to those found in the human disease, including ataxia and retinal defects (15,43). Current models suggest that the mutant proteins have adverse (17), but other studies indicate that poly-Q expanded Ataxin-7 proteins inhibit Gcn5 functions (25,30).…”

Section: Discussionmentioning

confidence: 99%

Loss of Gcn5 Acetyltransferase Activity Leads to Neural Tube Closure Defects and Exencephaly in Mouse Embryos

Bu¹,

Evrard²,

Lozano

et al. 2007

Molecular and Cellular Biology

123

117

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Gcn5 was the first transcription-related histone acetyltransferase (HAT) to be identified. However, the functions of this enzyme in mammalian cells remain poorly defined. Deletion of Gcn5 in mice leads to early embryonic lethality with increased apoptosis in mesodermal lineages. Here we show that deletion of p53 allows Gcn5 −/− embryos to survive longer, but Gcn5 −/− p53 −/− embryos still die in midgestation. Interestingly, embryos homozygous for point mutations in the Gcn5 catalytic domain survive significantly longer than Gcn5 −/− or Gcn5 −/− p53 −/− mice. In contrast to Gcn5 −/− embryos, Gcn5 hat/hat embryos do not exhibit increased apoptosis but do exhibit severe cranial neural tube closure defects and exencephaly. Together, our results indicate that Gcn5 has important, HAT-independent functions in early development and that Gcn5 acetyltransferase activity is required for cranial neural tube closure in the mouse.

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“…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).…”

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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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Insights into the molecular basis of polyglutamine neurodegeneration from studies of a spinocerebellar ataxia type 7 mouse model

Cited by 12 publications

References 76 publications

The dynamics of early-state transcriptional changes and aggregate formation in a Huntington’s disease cell model

The dynamics of early-state transcriptional changes and aggregate formation in a Huntington’s disease cell model

Loss of Gcn5 Acetyltransferase Activity Leads to Neural Tube Closure Defects and Exencephaly in Mouse Embryos

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

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