The Experts below are selected from a list of 4335 Experts worldwide ranked by ideXlab platform
Dominique Helmlinger - One of the best experts on this subject based on the ideXlab platform.
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Transcriptional alterations and chromatin remodeling in polyglutamine diseases.
Trends in Genetics, 2006Co-Authors: Dominique Helmlinger, Laszlo Tora, Didier DevysAbstract:Transcriptional dysregulation is now thought to be a common feature of polyglutamine disorders, including the spinocerebellar ataxias (SCAs). However, the precise causes of transcriptional alterations and how they relate to the observed phenotype remain elusive. Transcriptional impairment differs in different diseases, possibly reflecting the specific functions of the disease-causing proteins. The SCA7 gene product, Ataxin-7, is a subunit of a transcriptional coactivator complex (called STAGA or TFTC) that has histone acetyltransferase activity. Studies on the effect of mutant Ataxin-7 on STAGA function suggest that chromatin remodeling and transcriptional alterations are key pathologic events in SCA type 7. These studies could reveal how polyglutamine expansions alter the transcriptional regulation of genes required for neuronal function.
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Glutamine-expanded Ataxin-7 alters TFTC/STAGA recruitment and chromatin structure leading to photoreceptor dysfunction.
PLOS Biology, 2006Co-Authors: Dominique Helmlinger, Sara Hardy, Gretta Abou-sleymane, Adrien Eberlin, Aaron B. Bowman, Anne Gansmüller, Huda Y. Zoghbi, Serge Picaud, Yvon Trottier, Laszlo ToraAbstract:Spinocerebellar ataxia type 7 (SCA7) is one of several inherited neurodegenerative disorders caused by a polyglutamine (polyQ) expansion, but it is the only one in which the retina is affected. Increasing evidence suggests that transcriptional alterations contribute to polyQ pathogenesis, although the mechanism is unclear. We previously demonstrated that theSCA7 gene product, Ataxin-7 (ATXN7), is a subunit of the GCN5 histone acetyltransferase–containing coactivator complexes TFTC/STAGA. We show here that TFTC/STAGA complexes purified from SCA7 mice have normal TRRAP, GCN5, TAF12, and SPT3 levels and that their histone or nucleosomal acetylation activities are unaffected. However, rod photoreceptors from SCA7 mouse models showed severe chromatin decondensation. In agreement, polyQ-expanded Ataxin-7 induced histone H3 hyperacetylation, resulting from an increased recruitment of TFTC/STAGA to specific promoters. Surprisingly, hyperacetylated genes were transcriptionally down-regulated, and expression analysis revealed that nearly all rod-specific genes were affected, leading to visual impairment in SCA7 mice. In conclusion, we describe here a set of events accounting for SCA7 pathogenesis in the retina, in which polyQ-expanded ATXN7 deregulated TFTC/STAGA recruitment to a subset of genes specifically expressed in rod photoreceptors, leading to chromatin alterations and consequent progressive loss of rod photoreceptor function.
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Glutamine-Expanded Ataxin-7 Alters TFTC/STAGA Recruitment and Chromatin Structure Leading to Photoreceptor Dysfunction
PLoS Biology, 2006Co-Authors: Dominique Helmlinger, Sara Hardy, Gretta Abou-sleymane, Adrien Eberlin, Anne Gansmüller, Serge Picaud, Yvon Trottier, Aaron Bowman, Huda Zoghbi, Laszlo ToraAbstract:Spinocerebellar ataxia type 7 (SCA7) is one of several inherited neurodegenerative disorders caused by a polyglutamine (polyQ) expansion, but it is the only one in which the retina is affected. Increasing evidence suggests that transcriptional alterations contribute to polyQ pathogenesis, although the mechanism is unclear. We previously demonstrated that the SCA7 gene product, Ataxin-7 (ATXN7), is a subunit of the GCN5 histone acetyltransferase-containing coactivator complexes TFTC/STAGA. We show here that TFTC/STAGA complexes purified from SCA7 mice have normal TRRAP, GCN5, TAF12, and SPT3 levels and that their histone or nucleosomal acetylation activities are unaffected. However, rod photoreceptors from SCA7 mouse models showed severe chromatin decondensation. In agreement, polyQ-expanded Ataxin-7 induced histone H3 hyperacetylation, resulting from an increased recruitment of TFTC/STAGA to specific promoters. Surprisingly, hyperacetylated genes were transcriptionally down-regulated, and expression analysis revealed that nearly all rod-specific genes were affected, leading to visual impairment in SCA7 mice. In conclusion, we describe here a set of events accounting for SCA7 pathogenesis in the retina, in which polyQ-expanded ATXN7 deregulated TFTC/STAGA recruitment to a subset of genes specifically expressed in rod photoreceptors, leading to chromatin alterations and consequent progressive loss of rod photoreceptor function. Citation: Helmlinger D, Hardy S, Abou-Sleymane G, Eberlin A, Bowman AB, et al. (2006) Glutamine-expanded Ataxin-7 alters TFTC/STAGA recruitment and chromatin structure leading to photoreceptor dysfunction. PLoS Biol 4(3): e67.
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glutamine expanded Ataxin 7 alters tftc staga recruitment and chromatin structure leading to photoreceptor dysfunction
PLOS Biology, 2006Co-Authors: Dominique Helmlinger, Sara Hardy, Adrien Eberlin, Aaron B. Bowman, Anne Gansmüller, Huda Y. Zoghbi, Serge Picaud, Yvon Trottier, Gretta Abousleymane, Laszlo ToraAbstract:Spinocerebellar ataxia type 7 (SCA7) is one of several inherited neurodegenerative disorders caused by a polyglutamine (polyQ) expansion, but it is the only one in which the retina is affected. Increasing evidence suggests that transcriptional alterations contribute to polyQ pathogenesis, although the mechanism is unclear. We previously demonstrated that theSCA7 gene product, Ataxin-7 (ATXN7), is a subunit of the GCN5 histone acetyltransferase–containing coactivator complexes TFTC/STAGA. We show here that TFTC/STAGA complexes purified from SCA7 mice have normal TRRAP, GCN5, TAF12, and SPT3 levels and that their histone or nucleosomal acetylation activities are unaffected. However, rod photoreceptors from SCA7 mouse models showed severe chromatin decondensation. In agreement, polyQ-expanded Ataxin-7 induced histone H3 hyperacetylation, resulting from an increased recruitment of TFTC/STAGA to specific promoters. Surprisingly, hyperacetylated genes were transcriptionally down-regulated, and expression analysis revealed that nearly all rod-specific genes were affected, leading to visual impairment in SCA7 mice. In conclusion, we describe here a set of events accounting for SCA7 pathogenesis in the retina, in which polyQ-expanded ATXN7 deregulated TFTC/STAGA recruitment to a subset of genes specifically expressed in rod photoreceptors, leading to chromatin alterations and consequent progressive loss of rod photoreceptor function.
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Both normal and polyglutamine- expanded Ataxin-7 are components of TFTC-type GCN5 histone acetyltransferase- containing complexes.
Biochemical Society symposium, 2006Co-Authors: Dominique Helmlinger, Sara Hardy, Adrien Eberlin, Didier Devys, Laszlo ToraAbstract:SCA7 (spinocerebellar ataxia type 7) is a neurodegenerative disorder caused by a CAG repeat expansion in the SCA7 gene that leads to elongation of a polyglutamine tract in Ataxin-7, a protein of unknown function. Sgf73, a putative yeast orthologue of Ataxin-7, has been identified as a new component of the yeast SAGA (Spt/Ada/Gcn5 acetyltransferase) multisubunit complex, a co-activator required for the transcription of a subset of RNA polymerase II-dependent genes. We show here that Ataxin-7 is an integral component of mammalian SAGA-like complexes, i.e. the TFTC [TBP (TATA-binding protein)-free TAF (TBP-associated factor) complex] and the STAGA (SPT3/TAF9/GCN5 acetyltransferase) complex. In agreement with this, immunoprecipitation of Ataxin-7 retained a histone acetyltransferase activity characteristic of TFTC-like complexes. Moreover, polyglutamine expansion in Ataxin-7 did not affect its incorporation into TFTCs/STAGA complexes purified from cells from a SCA7 patient. We demonstrate here that Ataxin-7 is the human orthologue of a the yeast SAGA Sgf73 subunit, and is a bona fide subunit of human TFTC-like transcriptional complexes.
Laszlo Tora - One of the best experts on this subject based on the ideXlab platform.
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Transcriptional alterations and chromatin remodeling in polyglutamine diseases.
Trends in Genetics, 2006Co-Authors: Dominique Helmlinger, Laszlo Tora, Didier DevysAbstract:Transcriptional dysregulation is now thought to be a common feature of polyglutamine disorders, including the spinocerebellar ataxias (SCAs). However, the precise causes of transcriptional alterations and how they relate to the observed phenotype remain elusive. Transcriptional impairment differs in different diseases, possibly reflecting the specific functions of the disease-causing proteins. The SCA7 gene product, Ataxin-7, is a subunit of a transcriptional coactivator complex (called STAGA or TFTC) that has histone acetyltransferase activity. Studies on the effect of mutant Ataxin-7 on STAGA function suggest that chromatin remodeling and transcriptional alterations are key pathologic events in SCA type 7. These studies could reveal how polyglutamine expansions alter the transcriptional regulation of genes required for neuronal function.
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Glutamine-expanded Ataxin-7 alters TFTC/STAGA recruitment and chromatin structure leading to photoreceptor dysfunction.
PLOS Biology, 2006Co-Authors: Dominique Helmlinger, Sara Hardy, Gretta Abou-sleymane, Adrien Eberlin, Aaron B. Bowman, Anne Gansmüller, Huda Y. Zoghbi, Serge Picaud, Yvon Trottier, Laszlo ToraAbstract:Spinocerebellar ataxia type 7 (SCA7) is one of several inherited neurodegenerative disorders caused by a polyglutamine (polyQ) expansion, but it is the only one in which the retina is affected. Increasing evidence suggests that transcriptional alterations contribute to polyQ pathogenesis, although the mechanism is unclear. We previously demonstrated that theSCA7 gene product, Ataxin-7 (ATXN7), is a subunit of the GCN5 histone acetyltransferase–containing coactivator complexes TFTC/STAGA. We show here that TFTC/STAGA complexes purified from SCA7 mice have normal TRRAP, GCN5, TAF12, and SPT3 levels and that their histone or nucleosomal acetylation activities are unaffected. However, rod photoreceptors from SCA7 mouse models showed severe chromatin decondensation. In agreement, polyQ-expanded Ataxin-7 induced histone H3 hyperacetylation, resulting from an increased recruitment of TFTC/STAGA to specific promoters. Surprisingly, hyperacetylated genes were transcriptionally down-regulated, and expression analysis revealed that nearly all rod-specific genes were affected, leading to visual impairment in SCA7 mice. In conclusion, we describe here a set of events accounting for SCA7 pathogenesis in the retina, in which polyQ-expanded ATXN7 deregulated TFTC/STAGA recruitment to a subset of genes specifically expressed in rod photoreceptors, leading to chromatin alterations and consequent progressive loss of rod photoreceptor function.
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Glutamine-Expanded Ataxin-7 Alters TFTC/STAGA Recruitment and Chromatin Structure Leading to Photoreceptor Dysfunction
PLoS Biology, 2006Co-Authors: Dominique Helmlinger, Sara Hardy, Gretta Abou-sleymane, Adrien Eberlin, Anne Gansmüller, Serge Picaud, Yvon Trottier, Aaron Bowman, Huda Zoghbi, Laszlo ToraAbstract:Spinocerebellar ataxia type 7 (SCA7) is one of several inherited neurodegenerative disorders caused by a polyglutamine (polyQ) expansion, but it is the only one in which the retina is affected. Increasing evidence suggests that transcriptional alterations contribute to polyQ pathogenesis, although the mechanism is unclear. We previously demonstrated that the SCA7 gene product, Ataxin-7 (ATXN7), is a subunit of the GCN5 histone acetyltransferase-containing coactivator complexes TFTC/STAGA. We show here that TFTC/STAGA complexes purified from SCA7 mice have normal TRRAP, GCN5, TAF12, and SPT3 levels and that their histone or nucleosomal acetylation activities are unaffected. However, rod photoreceptors from SCA7 mouse models showed severe chromatin decondensation. In agreement, polyQ-expanded Ataxin-7 induced histone H3 hyperacetylation, resulting from an increased recruitment of TFTC/STAGA to specific promoters. Surprisingly, hyperacetylated genes were transcriptionally down-regulated, and expression analysis revealed that nearly all rod-specific genes were affected, leading to visual impairment in SCA7 mice. In conclusion, we describe here a set of events accounting for SCA7 pathogenesis in the retina, in which polyQ-expanded ATXN7 deregulated TFTC/STAGA recruitment to a subset of genes specifically expressed in rod photoreceptors, leading to chromatin alterations and consequent progressive loss of rod photoreceptor function. Citation: Helmlinger D, Hardy S, Abou-Sleymane G, Eberlin A, Bowman AB, et al. (2006) Glutamine-expanded Ataxin-7 alters TFTC/STAGA recruitment and chromatin structure leading to photoreceptor dysfunction. PLoS Biol 4(3): e67.
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glutamine expanded Ataxin 7 alters tftc staga recruitment and chromatin structure leading to photoreceptor dysfunction
PLOS Biology, 2006Co-Authors: Dominique Helmlinger, Sara Hardy, Adrien Eberlin, Aaron B. Bowman, Anne Gansmüller, Huda Y. Zoghbi, Serge Picaud, Yvon Trottier, Gretta Abousleymane, Laszlo ToraAbstract:Spinocerebellar ataxia type 7 (SCA7) is one of several inherited neurodegenerative disorders caused by a polyglutamine (polyQ) expansion, but it is the only one in which the retina is affected. Increasing evidence suggests that transcriptional alterations contribute to polyQ pathogenesis, although the mechanism is unclear. We previously demonstrated that theSCA7 gene product, Ataxin-7 (ATXN7), is a subunit of the GCN5 histone acetyltransferase–containing coactivator complexes TFTC/STAGA. We show here that TFTC/STAGA complexes purified from SCA7 mice have normal TRRAP, GCN5, TAF12, and SPT3 levels and that their histone or nucleosomal acetylation activities are unaffected. However, rod photoreceptors from SCA7 mouse models showed severe chromatin decondensation. In agreement, polyQ-expanded Ataxin-7 induced histone H3 hyperacetylation, resulting from an increased recruitment of TFTC/STAGA to specific promoters. Surprisingly, hyperacetylated genes were transcriptionally down-regulated, and expression analysis revealed that nearly all rod-specific genes were affected, leading to visual impairment in SCA7 mice. In conclusion, we describe here a set of events accounting for SCA7 pathogenesis in the retina, in which polyQ-expanded ATXN7 deregulated TFTC/STAGA recruitment to a subset of genes specifically expressed in rod photoreceptors, leading to chromatin alterations and consequent progressive loss of rod photoreceptor function.
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Both normal and polyglutamine- expanded Ataxin-7 are components of TFTC-type GCN5 histone acetyltransferase- containing complexes.
Biochemical Society symposium, 2006Co-Authors: Dominique Helmlinger, Sara Hardy, Adrien Eberlin, Didier Devys, Laszlo ToraAbstract:SCA7 (spinocerebellar ataxia type 7) is a neurodegenerative disorder caused by a CAG repeat expansion in the SCA7 gene that leads to elongation of a polyglutamine tract in Ataxin-7, a protein of unknown function. Sgf73, a putative yeast orthologue of Ataxin-7, has been identified as a new component of the yeast SAGA (Spt/Ada/Gcn5 acetyltransferase) multisubunit complex, a co-activator required for the transcription of a subset of RNA polymerase II-dependent genes. We show here that Ataxin-7 is an integral component of mammalian SAGA-like complexes, i.e. the TFTC [TBP (TATA-binding protein)-free TAF (TBP-associated factor) complex] and the STAGA (SPT3/TAF9/GCN5 acetyltransferase) complex. In agreement with this, immunoprecipitation of Ataxin-7 retained a histone acetyltransferase activity characteristic of TFTC-like complexes. Moreover, polyglutamine expansion in Ataxin-7 did not affect its incorporation into TFTCs/STAGA complexes purified from cells from a SCA7 patient. We demonstrate here that Ataxin-7 is the human orthologue of a the yeast SAGA Sgf73 subunit, and is a bona fide subunit of human TFTC-like transcriptional complexes.
Yvon Trottier - One of the best experts on this subject based on the ideXlab platform.
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Loss of zebrafish Ataxin-7, a SAGA subunit responsible for SCA7 retinopathy, causes ocular coloboma and malformation of photoreceptors.
Human molecular genetics, 2018Co-Authors: Samantha Carrillo-rosas, Chantal Weber, Alice Karam, Lorraine Fievet, Nadia Messaddeq, Yvon TrottierAbstract:Polyglutamine (polyQ) expansion in Ataxin-7 (ATXN7) results in spinocerebellar ataxia type 7 (SCA7) and causes visual impairment. SCA7 photoreceptors progressively lose their outer segments (OSs), a structure essential for their visual function. ATXN7 is a subunit of the transcriptional coactivator Spt-Ada-Gcn5 Acetyltransferase complex, implicated in the development of the visual system in flies. To determine the function of ATXN7 in the vertebrate eye, we have inactivated ATXN7 in zebrafish. While ATXN7 depletion in flies led to gross retinal degeneration, in zebrafish, it primarily results in ocular coloboma, a structural malformation responsible for pediatric visual impairment in humans. ATXN7 inactivation leads to elevated Hedgehog signaling in the forebrain, causing an alteration of proximo-distal patterning of the optic vesicle during early eye development and coloboma. At later developmental stages, malformations of photoreceptors due to incomplete formation of their OSs are observed and correlate with altered expression of crx, a key transcription factor involved in the formation of photoreceptor OS. Therefore, we propose that a primary toxic effect of polyQ expansion is the alteration of ATXN7 function in the daily renewal of OS in SCA7. Together, our data indicate that ATXN7 plays an essential role in vertebrate eye morphogenesis and photoreceptor differentiation, and its loss of function may contribute to the development of human coloboma.
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gain and loss of function mutations of Ataxin 7 cause cilia pathology in mouse and zebrafish models
Cilia, 2015Co-Authors: Alice Karam, Chantal Weber, Rita R Ferreira, Laurette Morle, Julien Vermot, Yvon TrottierAbstract:Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disease characterized by progressive neuronal loss in the cerebellum and associated structures, leading to cerebellar ataxia, dysarthria and dysphagia. Additional non-cerebellar symptoms are present at variable frequencies, including visual impairment affecting 83% of patients that is caused by cone and rod photoreceptor degeneration and hearing loss concerning 24% of patients. SCA7 is caused by a toxic polyglutamine expansion in Ataxin-7, a known subunit of the transcriptional co-regulator SAGA/TFTC complex. Transcriptional alterations are observed in SCA7, however, the disease mechanism is yet unclear. Ataxin-7 is also present in the cytoplasm of neurons, where its function is unknown. Here, we show for the first time that Ataxin-7 is a bona fide component of centrosomes and is present in diverse types of mammalian cilia, including primary, motile and photoreceptor sensory cilia. We provide evidence that Ataxin-7 loss of function causes a large spectrum of ciliary-related morphological and functional phenotypes in zebrafish, and that human Ataxin-7 is able to rescue the cilia phenotypes, demonstrating that Ataxin-7 has an essential, evolutionarily conserved function in cilia. Strikingly, Ataxin-7 is progressively lost from photoreceptor cilia in SCA7 mouse models, correlating with ciliary defects and photoreceptor degeneration. Finally, we found that expression of polyQ-expanded Ataxin-7, like Ataxin-7 loss of function, leads to ciliary dysfunctions in zebrafish. Our study thus provides new insight into the function of Ataxin-7 and opens novel perspective in the understanding of SCA7 pathogenesis.
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PML clastosomes prevent nuclear accumulation of mutant Ataxin-7 and other polyglutamine proteins
The Journal of cell biology, 2006Co-Authors: Alexandre Janer, Yvon Trottier, Merle Ruberg, Hiroto Fujigasaki, Elodie Martin, Marie-paule Muriel, Morwena Latouche, Alexis Brice, Annie SittlerAbstract:The pathogenesis of spinocerebellar ataxia type 7 and other neurodegenerative polyglutamine (polyQ) disorders correlates with the aberrant accumulation of toxic polyQ-expanded proteins in the nucleus. Promyelocytic leukemia protein (PML) nuclear bodies are often present in polyQ aggregates, but their relation to pathogenesis is unclear. We show that expression of PML isoform IV leads to the formation of distinct nuclear bodies enriched in components of the ubiquitin-proteasome system. These bodies recruit soluble mutant Ataxin-7 and promote its degradation by proteasome-dependent proteolysis, thus preventing the aggregate formation. Inversely, disruption of the endogenous nuclear bodies with cadmium increases the nuclear accumulation and aggregation of mutant Ataxin-7, demonstrating their role in Ataxin-7 turnover. Interestingly, beta-interferon treatment, which induces the expression of endogenous PML IV, prevents the accumulation of transiently expressed mutant Ataxin-7 without affecting the level of the endogenous wild-type protein. Therefore, clastosomes represent a potential therapeutic target for preventing polyQ disorders.
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Glutamine-expanded Ataxin-7 alters TFTC/STAGA recruitment and chromatin structure leading to photoreceptor dysfunction.
PLOS Biology, 2006Co-Authors: Dominique Helmlinger, Sara Hardy, Gretta Abou-sleymane, Adrien Eberlin, Aaron B. Bowman, Anne Gansmüller, Huda Y. Zoghbi, Serge Picaud, Yvon Trottier, Laszlo ToraAbstract:Spinocerebellar ataxia type 7 (SCA7) is one of several inherited neurodegenerative disorders caused by a polyglutamine (polyQ) expansion, but it is the only one in which the retina is affected. Increasing evidence suggests that transcriptional alterations contribute to polyQ pathogenesis, although the mechanism is unclear. We previously demonstrated that theSCA7 gene product, Ataxin-7 (ATXN7), is a subunit of the GCN5 histone acetyltransferase–containing coactivator complexes TFTC/STAGA. We show here that TFTC/STAGA complexes purified from SCA7 mice have normal TRRAP, GCN5, TAF12, and SPT3 levels and that their histone or nucleosomal acetylation activities are unaffected. However, rod photoreceptors from SCA7 mouse models showed severe chromatin decondensation. In agreement, polyQ-expanded Ataxin-7 induced histone H3 hyperacetylation, resulting from an increased recruitment of TFTC/STAGA to specific promoters. Surprisingly, hyperacetylated genes were transcriptionally down-regulated, and expression analysis revealed that nearly all rod-specific genes were affected, leading to visual impairment in SCA7 mice. In conclusion, we describe here a set of events accounting for SCA7 pathogenesis in the retina, in which polyQ-expanded ATXN7 deregulated TFTC/STAGA recruitment to a subset of genes specifically expressed in rod photoreceptors, leading to chromatin alterations and consequent progressive loss of rod photoreceptor function.
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Glutamine-Expanded Ataxin-7 Alters TFTC/STAGA Recruitment and Chromatin Structure Leading to Photoreceptor Dysfunction
PLoS Biology, 2006Co-Authors: Dominique Helmlinger, Sara Hardy, Gretta Abou-sleymane, Adrien Eberlin, Anne Gansmüller, Serge Picaud, Yvon Trottier, Aaron Bowman, Huda Zoghbi, Laszlo ToraAbstract:Spinocerebellar ataxia type 7 (SCA7) is one of several inherited neurodegenerative disorders caused by a polyglutamine (polyQ) expansion, but it is the only one in which the retina is affected. Increasing evidence suggests that transcriptional alterations contribute to polyQ pathogenesis, although the mechanism is unclear. We previously demonstrated that the SCA7 gene product, Ataxin-7 (ATXN7), is a subunit of the GCN5 histone acetyltransferase-containing coactivator complexes TFTC/STAGA. We show here that TFTC/STAGA complexes purified from SCA7 mice have normal TRRAP, GCN5, TAF12, and SPT3 levels and that their histone or nucleosomal acetylation activities are unaffected. However, rod photoreceptors from SCA7 mouse models showed severe chromatin decondensation. In agreement, polyQ-expanded Ataxin-7 induced histone H3 hyperacetylation, resulting from an increased recruitment of TFTC/STAGA to specific promoters. Surprisingly, hyperacetylated genes were transcriptionally down-regulated, and expression analysis revealed that nearly all rod-specific genes were affected, leading to visual impairment in SCA7 mice. In conclusion, we describe here a set of events accounting for SCA7 pathogenesis in the retina, in which polyQ-expanded ATXN7 deregulated TFTC/STAGA recruitment to a subset of genes specifically expressed in rod photoreceptors, leading to chromatin alterations and consequent progressive loss of rod photoreceptor function. Citation: Helmlinger D, Hardy S, Abou-Sleymane G, Eberlin A, Bowman AB, et al. (2006) Glutamine-expanded Ataxin-7 alters TFTC/STAGA recruitment and chromatin structure leading to photoreceptor dysfunction. PLoS Biol 4(3): e67.
Sara Hardy - One of the best experts on this subject based on the ideXlab platform.
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Glutamine-expanded Ataxin-7 alters TFTC/STAGA recruitment and chromatin structure leading to photoreceptor dysfunction.
PLOS Biology, 2006Co-Authors: Dominique Helmlinger, Sara Hardy, Gretta Abou-sleymane, Adrien Eberlin, Aaron B. Bowman, Anne Gansmüller, Huda Y. Zoghbi, Serge Picaud, Yvon Trottier, Laszlo ToraAbstract:Spinocerebellar ataxia type 7 (SCA7) is one of several inherited neurodegenerative disorders caused by a polyglutamine (polyQ) expansion, but it is the only one in which the retina is affected. Increasing evidence suggests that transcriptional alterations contribute to polyQ pathogenesis, although the mechanism is unclear. We previously demonstrated that theSCA7 gene product, Ataxin-7 (ATXN7), is a subunit of the GCN5 histone acetyltransferase–containing coactivator complexes TFTC/STAGA. We show here that TFTC/STAGA complexes purified from SCA7 mice have normal TRRAP, GCN5, TAF12, and SPT3 levels and that their histone or nucleosomal acetylation activities are unaffected. However, rod photoreceptors from SCA7 mouse models showed severe chromatin decondensation. In agreement, polyQ-expanded Ataxin-7 induced histone H3 hyperacetylation, resulting from an increased recruitment of TFTC/STAGA to specific promoters. Surprisingly, hyperacetylated genes were transcriptionally down-regulated, and expression analysis revealed that nearly all rod-specific genes were affected, leading to visual impairment in SCA7 mice. In conclusion, we describe here a set of events accounting for SCA7 pathogenesis in the retina, in which polyQ-expanded ATXN7 deregulated TFTC/STAGA recruitment to a subset of genes specifically expressed in rod photoreceptors, leading to chromatin alterations and consequent progressive loss of rod photoreceptor function.
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Glutamine-Expanded Ataxin-7 Alters TFTC/STAGA Recruitment and Chromatin Structure Leading to Photoreceptor Dysfunction
PLoS Biology, 2006Co-Authors: Dominique Helmlinger, Sara Hardy, Gretta Abou-sleymane, Adrien Eberlin, Anne Gansmüller, Serge Picaud, Yvon Trottier, Aaron Bowman, Huda Zoghbi, Laszlo ToraAbstract:Spinocerebellar ataxia type 7 (SCA7) is one of several inherited neurodegenerative disorders caused by a polyglutamine (polyQ) expansion, but it is the only one in which the retina is affected. Increasing evidence suggests that transcriptional alterations contribute to polyQ pathogenesis, although the mechanism is unclear. We previously demonstrated that the SCA7 gene product, Ataxin-7 (ATXN7), is a subunit of the GCN5 histone acetyltransferase-containing coactivator complexes TFTC/STAGA. We show here that TFTC/STAGA complexes purified from SCA7 mice have normal TRRAP, GCN5, TAF12, and SPT3 levels and that their histone or nucleosomal acetylation activities are unaffected. However, rod photoreceptors from SCA7 mouse models showed severe chromatin decondensation. In agreement, polyQ-expanded Ataxin-7 induced histone H3 hyperacetylation, resulting from an increased recruitment of TFTC/STAGA to specific promoters. Surprisingly, hyperacetylated genes were transcriptionally down-regulated, and expression analysis revealed that nearly all rod-specific genes were affected, leading to visual impairment in SCA7 mice. In conclusion, we describe here a set of events accounting for SCA7 pathogenesis in the retina, in which polyQ-expanded ATXN7 deregulated TFTC/STAGA recruitment to a subset of genes specifically expressed in rod photoreceptors, leading to chromatin alterations and consequent progressive loss of rod photoreceptor function. Citation: Helmlinger D, Hardy S, Abou-Sleymane G, Eberlin A, Bowman AB, et al. (2006) Glutamine-expanded Ataxin-7 alters TFTC/STAGA recruitment and chromatin structure leading to photoreceptor dysfunction. PLoS Biol 4(3): e67.
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glutamine expanded Ataxin 7 alters tftc staga recruitment and chromatin structure leading to photoreceptor dysfunction
PLOS Biology, 2006Co-Authors: Dominique Helmlinger, Sara Hardy, Adrien Eberlin, Aaron B. Bowman, Anne Gansmüller, Huda Y. Zoghbi, Serge Picaud, Yvon Trottier, Gretta Abousleymane, Laszlo ToraAbstract:Spinocerebellar ataxia type 7 (SCA7) is one of several inherited neurodegenerative disorders caused by a polyglutamine (polyQ) expansion, but it is the only one in which the retina is affected. Increasing evidence suggests that transcriptional alterations contribute to polyQ pathogenesis, although the mechanism is unclear. We previously demonstrated that theSCA7 gene product, Ataxin-7 (ATXN7), is a subunit of the GCN5 histone acetyltransferase–containing coactivator complexes TFTC/STAGA. We show here that TFTC/STAGA complexes purified from SCA7 mice have normal TRRAP, GCN5, TAF12, and SPT3 levels and that their histone or nucleosomal acetylation activities are unaffected. However, rod photoreceptors from SCA7 mouse models showed severe chromatin decondensation. In agreement, polyQ-expanded Ataxin-7 induced histone H3 hyperacetylation, resulting from an increased recruitment of TFTC/STAGA to specific promoters. Surprisingly, hyperacetylated genes were transcriptionally down-regulated, and expression analysis revealed that nearly all rod-specific genes were affected, leading to visual impairment in SCA7 mice. In conclusion, we describe here a set of events accounting for SCA7 pathogenesis in the retina, in which polyQ-expanded ATXN7 deregulated TFTC/STAGA recruitment to a subset of genes specifically expressed in rod photoreceptors, leading to chromatin alterations and consequent progressive loss of rod photoreceptor function.
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Both normal and polyglutamine- expanded Ataxin-7 are components of TFTC-type GCN5 histone acetyltransferase- containing complexes.
Biochemical Society symposium, 2006Co-Authors: Dominique Helmlinger, Sara Hardy, Adrien Eberlin, Didier Devys, Laszlo ToraAbstract:SCA7 (spinocerebellar ataxia type 7) is a neurodegenerative disorder caused by a CAG repeat expansion in the SCA7 gene that leads to elongation of a polyglutamine tract in Ataxin-7, a protein of unknown function. Sgf73, a putative yeast orthologue of Ataxin-7, has been identified as a new component of the yeast SAGA (Spt/Ada/Gcn5 acetyltransferase) multisubunit complex, a co-activator required for the transcription of a subset of RNA polymerase II-dependent genes. We show here that Ataxin-7 is an integral component of mammalian SAGA-like complexes, i.e. the TFTC [TBP (TATA-binding protein)-free TAF (TBP-associated factor) complex] and the STAGA (SPT3/TAF9/GCN5 acetyltransferase) complex. In agreement with this, immunoprecipitation of Ataxin-7 retained a histone acetyltransferase activity characteristic of TFTC-like complexes. Moreover, polyglutamine expansion in Ataxin-7 did not affect its incorporation into TFTCs/STAGA complexes purified from cells from a SCA7 patient. We demonstrate here that Ataxin-7 is the human orthologue of a the yeast SAGA Sgf73 subunit, and is a bona fide subunit of human TFTC-like transcriptional complexes.
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Both normal and polyglutamine- expanded Ataxin-7 are comp- onents of TFTC-type GCN5 histone acetyltransferase- containing complexes
Biochemical Society Symposia, 2006Co-Authors: Dominique Helmlinger, Sara Hardy, Adrien Eberlin, Didier Devys, Laszlo ToraAbstract:SCA7 (spinocerebellar ataxia type 7) is a neurodegenerative disorder caused by a CAG repeat expansion in the SCA7 gene that leads to elongation of a polyglutamine tract in Ataxin-7, a protein of unknown function. Sgf73, a putative yeast orthologue of Ataxin-7, has been identified as a new component of the yeast SAGA (Spt/Ada/Gcn5 acetyltransferase) multisubunit complex, a co-activator required for the transcription of a subset of RNA polymerase II-dependent genes. We show here that Ataxin-7 is an integral component of mammalian SAGA-like complexes, i.e. the TFTC [TBP (TATA-binding protein)-free TAF (TBP-associated factor) complex] and the STAGA (SPT3/TAF9/GCN5 acetyltransferase) complex. In agreement with this, immunoprecipitation of Ataxin-7 retained a histone acetyltransferase activity characteristic of TFTC-like complexes. Moreover, polyglutamine expansion in Ataxin-7 did not affect its incorporation into TFTCs/STAGA complexes purified from cells from a SCA7 patient. We demonstrate here that Ataxin-7 is the human orthologue of a the yeast SAGA Sgf73 subunit, and is a bona fide subunit of human TFTC-like transcriptional complexes.
Albert R. La Spada - One of the best experts on this subject based on the ideXlab platform.
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Proteolytic cleavage of Ataxin-7 promotes SCA7 retinal degeneration and neurological dysfunction
Human molecular genetics, 2015Co-Authors: Stephan J Guyenet, Sara K Custer, Bryce L Sopher, Amy Lin, Sylvia F. Chen, Albert R. La Spada, Shona S. Mookerjee, Lisa M EllerbyAbstract:The neurodegenerative disorder spinocerebellar ataxia type 7 (SCA7) is caused by a polyglutamine (polyQ) expansion in the Ataxin-7 protein, categorizing SCA7 as one member of a large class of heritable neurodegenerative proteinopathies. Cleavage of Ataxin-7 by the protease caspase-7 has been demonstrated in vitro, and the accumulation of proteolytic cleavage products in SCA7 patients and mouse models has been identified as an early pathological change. However, it remains unknown whether a causal relationship exists between Ataxin-7 proteolysis and in vivo SCA7 disease progression. To determine whether caspase cleavage is a critical event in SCA7 disease pathogenesis, we generated transgenic mice expressing polyQ-expanded Ataxin-7 with a second-site mutation (D266N) to prevent caspase-7 proteolysis. When we compared SCA7-D266N mice with SCA7 mice lacking the D266N mutation, we found that SCA7-D266N mice exhibited improved motor performance, reduced neurodegeneration and substantial lifespan extension. Our findings indicate that proteolysis at the D266 caspase-7 cleavage site is an important mediator of Ataxin-7 neurotoxicity, suggesting that inhibition of caspase-7 cleavage of polyQ-Ataxin-7 may be a promising therapeutic strategy for this untreatable disorder.
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Nonallele specific silencing of Ataxin-7 improves disease phenotypes in a mouse model of SCA7.
Molecular therapy : the journal of the American Society of Gene Therapy, 2014Co-Authors: Pavitra S. Ramachandran, Albert R. La Spada, Ryan L. Boudreau, Kellie A. Schaefer, Beverly L. DavidsonAbstract:Spinocerebellar ataxia type 7 (SCA7) is a late-onset neurodegenerative disease characterized by ataxia and vision loss with no effective treatments in the clinic. The most striking feature is the degeneration of Purkinje neurons of the cerebellum caused by the presence of polyglutamine-expanded Ataxin-7. Ataxin-7 is part of a transcriptional complex, and, in the setting of mutant Ataxin-7, there is misregulation of target genes. Here, we designed RNAi sequences to reduce the expression of both wildtype and mutant Ataxin-7 to test if reducing Ataxin-7 in Purkinje cells is both tolerated and beneficial in an animal model of SCA7. We observed sustained reduction of both wildtype and mutant Ataxin-7 as well as a significant improvement of ataxia phenotypes. Furthermore, we observed a reduction in cerebellar molecular layer thinning and nuclear inclusions, a hallmark of SCA7. In addition, we observed recovery of cerebellar transcripts whose expression is disrupted in the presence of mutant Ataxin-7. These data demonstrate that reduction of both wildtype and mutant Ataxin-7 by RNAi is well tolerated, and contrary to what may be expected from reducing a component of the Spt-Taf9-Gcn5 acetyltransferase complex, is efficacious in the SCA7 mouse.
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Reduction of mutant Ataxin-7 expression restores motor function and prevents cerebellar synaptic reorganization in a conditional mouse model of SCA7
Human molecular genetics, 2012Co-Authors: Stephanie A. Furrer, Gwenn A Garden, Bryce L Sopher, Mathini S. Mohanachandran, Sarah M. Waldherr, Vincent A. Damian, Travis D. Baughn, Kien Thiet Nguyen, Albert R. La SpadaAbstract:Spinocerebellar ataxia type 7 (SCA7) is a dominantly inherited neurodegenerative disorder caused by a CAG - polyglutamine (polyQ) repeat expansion in the Ataxin-7 gene. In polyQ disorders, synaptic dysfunction and neurodegeneration may develop prior to symptom onset. However, conditional expression studies of polyQ disease models demonstrate that suppression of gene expression can yield complete reversal of established behavioral abnormalities. To determine if SCA7 neurological and neurodegenerative phenotypes are reversible, we crossed PrP-floxed-SCA7-92Q BAC transgenic mice with a tamoxifen-inducible Cre recombinase transgenic line, CAGGS-Cre-ER™. PrP-floxed-SCA7-92Q BAC;CAGGS-Cre-ER™ bigenic mice were treated with a single dose of tamoxifen 1 month after the onset of detectable ataxia, which resulted in ~50% reduction of polyQ-Ataxin-7 expression. Tamoxifen treatment halted or reversed SCA7 motor symptoms, reduced Ataxin-7 aggregation in Purkinje cells (PCs), and prevented loss of climbing fiber (CF)-PC synapses in comparison to vehicle-treated bigenic animals and tamoxifen-treated PrP-floxed-SCA7-92Q BAC single transgenic mice. Despite this phenotype rescue, reduced Ataxin-7 expression did not result in full recovery of cerebellar molecular layer thickness or prevent Bergmann glia degeneration. These results demonstrate that suppression of mutant gene expression by only 50% in a polyQ disease model can have a significant impact on disease phenotypes, even when initiated after the onset of detectable behavioral deficits. The findings reported here are consistent with the emerging view that therapies aimed at reducing neurotoxic gene expression hold the potential to halt or reverse disease progression in afflicted patients, even after the onset of neurological disability.
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Ataxin-7 associates with microtubules and stabilizes the cytoskeletal network
Human molecular genetics, 2011Co-Authors: Yoko Nakamura, Albert R. La Spada, Kazuhiko Tagawa, Tsutomu Oka, Toshikazu Sasabe, Hikaru Ito, Hiroki Shiwaku, Hitoshi OkazawaAbstract:The spinocerebellar ataxia type 7 (SCA7) gene product, Ataxin-7 (ATXN7), localizes to the nucleus and has been shown to function as a component of the TATA-binding protein-free TAF-containing-SPT3-TAF9-GCN5-acetyltransferase transcription complex, although cytoplasmic localization of ATXN7 in affected neurons of human SCA7 patients has also been detected. Here, we define a physiological function for cytoplasmic ATXN7. Live imaging reveals that the intracellular distribution of ATXN7 dynamically changes and that ATXN7 distribution frequently shifts from the nucleus to the cytoplasm. Immunocytochemistry and immunoprecipitation demonstrate that cytoplasmic ATXN7 associates with microtubules (MTs), and expression of ATXN7 stabilizes MTs against nocodazole treatment, while ATXN7 knockdown enhances MT degradation. Interestingly, normal and mutant ATXN7 similarly associate with and equally stabilize MTs. Taken together, these findings provide a novel physiological function of ATXN7 in the regulation of cytoskeletal dynamics, and suggest that abnormal cytoskeletal regulation may contribute to SCA7 disease pathology.
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Spinocerebellar ataxia type 7 cerebellar disease requires the coordinated action of mutant Ataxin-7 in neurons and glia, and displays non-cell-autonomous bergmann glia degeneration.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011Co-Authors: Stephanie A. Furrer, Gwenn A Garden, Bryce L Sopher, Mathini S. Mohanachandran, Sarah M. Waldherr, Christopher H. Chang, Vincent A. Damian, Albert R. La SpadaAbstract:Spinocerebellar ataxia type 7 (SCA7) is a dominantly inherited disorder characterized by cerebellum and brainstem neurodegeneration. SCA7 is caused by a CAG/polyglutamine (polyQ) repeat expansion in the Ataxin-7 gene. We previously reported that directed expression of polyQ-Ataxin-7 in Bergmann glia (BG) in transgenic mice leads to ataxia and non-cell-autonomous Purkinje cell (PC) degeneration. To further define the cellular basis of SCA7, we derived a conditional inactivation mouse model by inserting a loxP-flanked Ataxin-7 cDNA with 92 repeats into the translational start site of the murine prion protein (PrP) gene in a bacterial artificial chromosome (BAC). The PrP-floxed-SCA7-92Q BAC mice developed neurological disease, and exhibited cerebellar degeneration and BG process loss. To inactivate polyQ-Ataxin-7 expression in specific cerebellar cell types, we crossed PrP-floxed-SCA7-92Q BAC mice with Gfa2-Cre transgenic mice (to direct Cre to BG) or Pcp2-Cre transgenic mice (which yields Cre in PCs and inferior olive). Excision of Ataxin-7 from BG partially rescued the behavioral phenotype, but did not prevent BG process loss or molecular layer thinning, while excision of Ataxin-7 from PCs and inferior olive provided significantly greater rescue and prevented both pathological changes, revealing a non-cell-autonomous basis for BG pathology. When we prevented expression of mutant Ataxin-7 in BG, PCs, and inferior olive by deriving Gfa2-Cre;Pcp2-Cre;PrP-floxed-SCA7-92Q BAC triple transgenic mice, we noted a dramatic improvement in SCA7 disease phenotypes. These findings indicate that SCA7 disease pathogenesis involves a convergence of alterations in a variety of different cell types to fully recapitulate the cerebellar degeneration.