InteractiveFly: GeneBrief

Ataxin 7: Biological Overview | References

Atxn7, a subunit of SAGA chromatin remodeling complex, is subject to polyglutamine expansion at the amino terminus, causing spinocerebellar ataxia type 7 (SCA7), a progressive retinal and neurodegenerative disease. Within SAGA, the Atxn7 amino terminus anchors Non-stop, a deubiquitinase, to the complex. To understand the scope of Atxn7-dependent regulation of Non-stop, substrates of the deubiquitinase were sought. This revealed Non-stop, dissociated from Atxn7, interacts with Arp2/3 and WAVE regulatory complexes (WRC), which control actin cytoskeleton assembly. There, Non-stop countered polyubiquitination and proteasomal degradation of WRC subunit SCAR. Dependent on conserved WRC interacting receptor sequences (WIRS), Non-stop augmentation increased protein levels, and directed subcellular localization, of SCAR, decreasing cell area and number of protrusions. In vivo, heterozygous mutation of SCAR did not significantly rescue knockdown of Atxn7, but heterozygous mutation of Atxn7 rescued haploinsufficiency of SCAR (Cloud, 2019).

Purification of Atxn7-containing complexes indicated that Atxn7 functions predominantly as a member of SAGA. In yeast, the Atxn7 orthologue, Sgf73, can be separated from SAGA along with the deubiquitinase module by the proteasome regulatory particle. Without Sgf73, the yeast deubiquitinase module is inactive. In higher eukaryotes, Atxn7 increases, but is not necessary for Non-stop/USP22 enzymatic activity in vitro. In Drosophila, loss of Atxn7 leads to a Non-stop over activity phenotype, with reduced levels of ubiquitinated H2B observed (Mohan, 2014). In this study, purification of Non-stop revealed the active SAGA DUBm associates with multi-protein complexes including WRC and Arp2/3 complexes separate from SAGA. SCAR was previously described to be regulated by a constant ubiquitination/deubiquitination mechanism. SCAR protein levels increased upon knockdown of Atxn7 and decreased upon knockdown of non-stop. Decreases in SCAR protein levels in the absence of non-stop required a functional proteasome (Cloud, 2019).

Conversely, overexpression of Non-stop in cells led to increased SCAR protein levels and this increased SCAR protein colocalized to subcellular compartments where Non-stop was found. Nuclear Arp2/3 and WRC have been linked to nuclear reprogramming during early development, immune system function, and general regulation of gene expression. Distortions of nuclear shape alter chromatin domain location within the nucleus, resulting in changes in gene expression. Nuclear pore stability is compromised in SAGA DUBm mutants, resulting in deficient mRNA export. Similarly, mutants of F-actin regulatory proteins, such as Wash, show nuclear pore loss. Non-stop may contribute to nuclear pore stability and mRNA export through multiple mechanisms (Cloud, 2019).

When the basis for this unexpected regulatory mechanism was examined, a series was uncovered of WIRS motifs conserved in number and distribution between flies and mammals. These sequences functionally modulate Non-stop ability to increase SCAR protein levels. Point mutants of each WIRS resulted in less SCAR protein per increase in Non-stop protein. WIRS mutant Non-stop retained the ability to incorporate into SAGA, indicating these are separation of function mutants (Cloud, 2019).

Overall, these findings suggest that the cell maintains a pool of Non-stop that can be made available to act distally from the larger SAGA complex to modulate SCAR protein levels (see Non-stop regulates SCAR protein levels and location). In yeast, the proteasome regulatory particle removes the DUBm from SAGA. In higher eukaryotes, caspase-7 cleaves Atxn7 at residues which would be expected to release the DUBm, although this remains to be shown explicitly. The mechanisms orchestrating entry and exit of the DUBm from SAGA remain to be explored (Cloud, 2019).

Quantification of Ataxin-3 and Ataxin-7 aggregates formed in vivo in Drosophila reveals a threshold of aggregated polyglutamine proteins associated with cellular toxicity

Polyglutamine diseases are nine dominantly inherited neurodegenerative pathologies caused by the expansion of a polyglutamine domain in a protein responsible for the disease. This expansion leads to protein aggregation, inclusion formation and toxicity. Despite numerous studies focusing on the subject, whether soluble polyglutamine proteins are responsible for toxicity or not remains debated. To focus on this matter, this study evaluated the level of soluble and insoluble truncated pathological Ataxin-3 in vivo in Drosophila, in presence or absence of two suppressors (i.e. Hsp70 and non-pathological Ataxin-3) and along aging. Suppressing truncated Ataxin-3-induced toxicity resulted in a lowered level of aggregated polyglutamine protein. Interestingly, aggregates accumulated as flies aged and reached a maximum level when cell death was detected. These results were similar with two other pathological polyglutamine proteins, namely truncated Ataxin-7 and full-length Ataxin-3. The data suggest that accumulation of insoluble aggregates beyond a critical threshold could be responsible for toxicity (Vinatier, 2105).

Loss of Drosophila Ataxin-7, a SAGA subunit, reduces H2B ubiquitination and leads to neural and retinal degeneration

The Spt-Ada-Gcn5-acetyltransferase (SAGA) chromatin-modifying complex possesses acetyltransferase and deubiquitinase activities. Within this modular complex, Ataxin-7 anchors the deubiquitinase activity to the larger complex. This study identified and characterized Drosophila Ataxin-7 (CG9866)and found that reduction of Ataxin-7 protein results in loss of components from the SAGA complex. In contrast to yeast, where loss of Ataxin-7 inactivates the deubiquitinase and results in increased H2B ubiquitination, loss of Ataxin-7 results in decreased H2B ubiquitination and H3K9 acetylation without affecting other histone marks. Interestingly, the effect on ubiquitination was conserved in human cells, suggesting a novel mechanism regulating histone deubiquitination in higher organisms. Consistent with this mechanism in vivo, this study found that a recombinant deubiquitinase module is active in the absence of Ataxin-7 in vitro. When the consequences of reduced Ataxin-7 were examined in vivo, it was found that flies exhibited pronounced neural and retinal degeneration, impaired movement, and early lethality (Mohan, 2014).

The Spt-Ada-Gcn5-acetyltransferase (SAGA) chromatin-modifying complex is a highly conserved 2-MDa protein complex comprised of ∼20 subunits. The complex is arranged in a modular fashion and contains two enzymatic activities: an acetyltransferase activity associated with the GCN5/Pcaf subunit and a deubiquitinase activity associated with the yUbp8/dNon-stop/hUsp22 subunit. In yeast, the ataxin-7 homolog is Sgf73, and studies have shown that it anchors the deubiquitinase module (which includes Sgf73, Sgf11, Sus1, and Ubp8) to the SAGA complex. Crystal structures and biochemical analysis of the yeast deubiquitinase module have shown that the N terminus of Sgf73 extends deep into the deubiquitinase module, intertwining between the components of the module to ensure an active conformation for the deubiquitinase. Without Sgf73, the deubiquitinase is inactive. The carefully orchestrated addition and removal of ubiquitin on H2B are important regulators of transcription. H2B monoubiquitination is a prerequisite for di- and trimethylation of H3K4 and H3K79, modifications associated with transcriptionally active chromatin (Mohan, 2014).

This study identified the gene product of CG9866 as the Drosophila homolog of ataxin-7 (Ataxin-7). Biochemical analysis, including affinity purification, multidimensional protein identification technology (MudPIT) proteomic analysis, and gel filtration chromatography, establish that Ataxin-7 is a stable component of the SAGA chromatin remodeling complex. Analysis of SAGA from Ataxin-7-deficient flies revealed the loss of components from the SAGA complex, consistent with a role for Ataxin-7 in anchoring the deubiquitinase module to the complex. In contrast to the increased H2Bub observed upon loss of ataxin-7 in yeast, this study observed a decrease in H2B ubiquitination in Drosophila with no associated changes in histone methylation and a reduction in the levels of H3K9 acetylation but not K3K14 acetylation. This surprising change in H2B ubiquitination was confirmed in human cells in which knockdown of human Ataxin-7 also resulted in decreased H2B ubiquitination. It is hypothesized that this decrease reflects the release of an active deubiquitinase module from SAGA and, consequently, loss of SAGA-associated regulation of the deubiquitinase activity. Consistent with this model, it was found that the deubiquitinase is enzymatically active when the complex is reconstituted in vitro even in the absence of Ataxin-7. An examination of flies with reduced expression of Ataxin-7 showed that loss of Ataxin-7 results in neural and retinal degeneration, impaired movement, and decreased life span (Mohan, 2014).

This study presents the first study of Drosophila Ataxin-7. Ataxin-7 shares primary amino acid sequence conservation with human Ataxin-7 and, accordingly, is also a member of the SAGA chromatin-modifying complex. SAGA subunits are lost in the absence of Ataxin-7, resulting in a global decrease in the levels of H2B ubiquitination and H3K9 acetylation without affecting H3K14ac, H3K4me2/3, or H3K79me3. Because Ataxin-7 associates with the intact SAGA complex and loss of Ataxin-7 results in fragmentation of the complex, this study explored whether decreased levels of H2B ubiquitination were due to release of an active deubiquitinase module from SAGA. Indeed, the deubiquitinase module assembled in vitro from purified Non-stop, E(y)2, and Sgf11 is enzymatically active and is unaffected by the presence or absence of Ataxin-7. In vivo, disruption of Ataxin-7 expression leads to severe neural and retinal degeneration, limited life span, and defective locomotion. These defects are at least in part due to elevated deubiquitinase activity, since loss of one copy of the Non-stop deubiquitinase suppresses the lethality of Ataxin-7 mutants (Mohan, 2014).

These results suggest a more elaborate mode of regulation of histone ubiquitination in higher eukaryotes than that found in yeast. Studies in Saccharomyces cerevisiae showed that the deubiquitinase module comprised of Sgf73, Ubp8, Sgf11, and Sus1 is arranged so that each member of the module is in contact with the other three, and these contacts establish an enzymatically active module. Truncation of the Sgf73 N terminus led to an enzymatically inactive module. In contrast, in Drosophila and in human cells, the presence of Ataxin-7 is not necessary for deubiquitinase activity, and, instead, loss of Ataxin-7 results in increased deubiquitination and reduced levels of H2B ubiquitination (Mohan, 2014).

Interestingly, it wa found that this decrease in H2B ubiquitination does not coincide with a decrease in H3K4me2/3 or H3K79me3. Previously, it was shown that H2B ubiquitination was necessary for recruitment of methyltransferases to place these marks, and reduction of the Drosophila Bre1 E3 ubiquitin ligase results in loss of both H2B ubiquitination and H3 methylation. If indeed H2B ubiquitination is required for H3 methylation, then the mark would have been placed and then removed post-methylation by the mistargeted deubiquitinase module. This suggests that methylation may not be affected by the loss of Ataxin-7 because the deubiquitinase acts after ubiquitination-dependent methylation has occurred. It is also possible that a high level of H2B ubiquitination is not required to target methyltransferases. Recently, it was shown in yeast that loss of Chd1 results in reductions in H2B ubiquitination without a corresponding loss of H3K4 or H3K79 trimethylation, suggesting that very low levels of H2B ubiquitination are enough to target methyltransferases. Alternatively, it is possible that another mechanism exists for targeting methyltransferases when levels of ubiquitinated H2B are low or absent. During muscle differentiation, the RNF20 ubiquitin ligase is depleted in differentiated myotubes, resulting in the absence of H2B ubiquitination, yet trimethylation of H3K4 and H3K79 is detected on chromatin lacking H2B ubiquitination. Recently, it was shown that transcription factors such as p53 along with p300 can recruit the SET1 histone methyltransferase complex independent of H2B ubiquitination (Mohan, 2014).

Mutation of different SAGA subunits does not necessarily result in changes in expression of the same sets of genes. Disrupting expression of subunits in the acetyltransferase module versus the deubiquitinase module affects a curiously divergent set of genes, indicating that different genes have varying requirements for each catalytic activity of the complex. A dissociated active deubiquitinase module may play a role in this sophisticated regulation, since a free ubiquitin protease module could act on ubiquitinated chromatin independent of SAGA recruitment and regulation. In yeast lacking Sgf73, Sus1 is released from SAGA but is still recruited to genes, albeit at a reduced level. Moreover, early reports identified USP22 as an H2Aub deubiquitinase acting on polycomb-regulated genes. In principal, SAGA may release subcomplexes to participate in diverse functions. It was recently shown in S. cerevisiae that the proteasome is capable of pulling the enzymatically active DUB module, including Sgf73, Sgf11, and Sus1, from SAGA, indicating that separation of SAGA may normally occur. Further investigation into the modularity of SAGA and its implications for transcriptional regulation in vivo may aid in understanding how this complex might provide a sophisticated mechanism for chromatin modification and gene regulation. In addition to direct chromatin modification, Non-stop and its homologs have also been shown to act on nonhistone proteins, and it is possible that nonhistone targets play a significant role in SCA7 pathology (Mohan, 2014).

SCA7 and other polyglutamine expansion diseases have divergent pathologies. These differences suggest that the function of the expanded protein is critical to the etiology of each disease. Unfortunately, there is currently a limited understanding of the molecular functions of the wild-type proteins and what role loss or gain of function might play in the characteristic patterns of neural degeneration found upon polyglutamine expansion. In initial studies examining the wild-type function of other SCA proteins, loss of the wild-type protein did not entirely phenocopy the polyglutamine expansion disease. For example, Ataxin-1 knockout mice do not show cerebellar or brainstem degeneration but do exhibit cognitive defects and ataxia. The observations of this study suggest that loss of Ataxin-7 function may play a role in SCA7 disease progression. Polyglutamine-expanded Ataxin-7 is resistant to proteolysis, accumulating in cells. At the same time, the wild-type protein is only produced from one genomic copy, and the resulting protein is subjected to normal proteolysis. Furthermore, the Ataxin-7 N terminus extends into the deubiquitinase module, and this region is subject to polyglutamine tract expansion. Polyglutamine-expanded Ataxin-7 is present in the larger SAGA complex, but the deubiquitinase module was not specifically analyzed in this model. It will be interesting to examine whether the deubiquitinase module is also recruited to the complex under these conditions and, if so, whether it is enzymatically active. If the deubiquitinase module does not form around the expanded Ataxin-7, tracking the localization of this module may be insightful. It will also be interesting to examine the potential regulation of the deubiquitinase module independent of SAGA under wild-type conditions. Understanding what might trigger release of the module from the larger complex will be critical to understanding the role of SAGA in neural and retinal stability (Mohan, 2014).

A conditional pan-neuronal Drosophila model of spinocerebellar ataxia 7 with a reversible adult phenotype suitable for identifying modifier genes

Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the ataxin 7 (ATXN7) protein, a member of a multiprotein complex involved in histone acetylation. This study created a conditional Drosophila model of SCA7 in which expression of truncated ATXN7 (ATXN7T) with a pathogenic polyQ expansion is induced in neurons in adult flies. In this model, mutant ATXN7T accumulated in neuronal intranuclear inclusions containing ubiquitin, the 19S proteasome subunit, and HSP70 (heat shock protein 70), as in patients. Aggregation was accompanied by a decrease in locomotion and lifespan but limited neuronal death. Disaggregation of the inclusions, when expression of expanded ATXN7T was stopped, correlated with improved locomotor function and increased lifespan, suggesting that the pathology may respond to treatment. Lifespan was then used as a quantitative marker in a candidate gene approach to validate the interest of the model and to identify generic modulators of polyQ toxicity and specific modifiers of SCA7. Several molecular pathways identified in this focused screen (proteasome function, unfolded protein stress, caspase-dependent apoptosis, and histone acetylation) were further studied in primary neuronal cultures. Sodium butyrate, a histone deacetylase inhibitor, improved the survival time of the neurons. This model is therefore a powerful tool for studying SCA7 and for the development of potential therapies for polyQ diseases (Latouche, 2007).

SCA7 Mouse Cerebellar Pathology Reveals Preferential Downregulation of Key Purkinje Cell-Identity Genes and Shared Disease Signature with SCA1 and SCA2

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease mainly characterized by motor incoordination because of progressive cerebellar degeneration. SCA7 is caused by polyglutamine expansion in ATXN7, a subunit of the transcriptional coactivator SAGA, which harbors histone modification activities. Polyglutamine expansions in specific proteins are also responsible for SCA1-SCA3, SCA6, and SCA17; however, the converging and diverging pathomechanisms remain poorly understood. Using a new SCA7 knock-in mouse, SCA7(140Q/5Q), this study analyzed gene expression in the cerebellum and assigned gene deregulation to specific cell types using published datasets. Gene deregulation affects all cerebellar cell types, although at variable degree, and correlates with alterations of SAGA-dependent epigenetic marks. Purkinje cells (PCs) are by far the most affected neurons and show reduced expression of 83 cell-type identity genes, including these critical for their spontaneous firing activity and synaptic functions. PC gene downregulation precedes morphologic alterations, pacemaker dysfunction, and motor incoordination. Strikingly, most PC genes downregulated in SCA7 have also decreased expression in SCA1 and SCA2 mice, revealing converging pathomechanisms and a common disease signature involving cGMP-PKG and phosphatidylinositol signaling pathways and LTD. This study thus points out molecular targets for therapeutic development, which may prove beneficial for several SCAs. Furthermore, it was shown that SCA7(140Q/5Q) males and females exhibit the major disease features observed in patients, including cerebellar damage, cerebral atrophy, peripheral nerves pathology, and photoreceptor dystrophy, which account for progressive impairment of behavior, motor, and visual functions. SCA7(140Q/5Q) mice represent an accurate model for the investigation of different aspects of SCA7 pathogenesis (Niewiadomska-Cimicka, 2021).

Histone H2Bub1 deubiquitylation is essential for mouse development, but does not regulate global RNA polymerase II transcription

Co-activator complexes dynamically deposit post-translational modifications (PTMs) on histones, or remove them, to regulate chromatin accessibility and/or to create/erase docking surfaces for proteins that recognize histone PTMs. SAGA (Spt-Ada-Gcn5 Acetyltransferase) is an evolutionary conserved multisubunit co-activator complex with modular organization. The deubiquitylation module (DUB) of mammalian SAGA complex is composed of the ubiquitin-specific protease 22 (USP22) and three adaptor proteins, ATXN7, ATXN7L3 and ENY2, which are all needed for the full activity of the USP22 enzyme to remove monoubiquitin (ub1) from histone H2B. Two additional USP22-related ubiquitin hydrolases (called USP27X or USP51) have been described to form alternative DUBs with ATXN7L3 and ENY2, which can also deubiquitylate H2Bub1. This study reports that USP22 and ATXN7L3 are essential for normal embryonic development of mice, however their requirements are not identical during this process, as Atxn7l3(-/-) embryos show developmental delay already at embryonic day (E) 7.5, while Usp22(-/-) embryos are normal at this stage, but die at E14.5. Global histone H2Bub1 levels were only slightly affected in Usp22 null embryos, in contrast H2Bub1 levels were strongly increased in Atxn7l3 null embryos and derived cell lines. Transcriptomic analyses carried out from wild type and Atxn7l3(-/-) mouse embryonic stem cells (mESCs), or primary mouse embryonic fibroblasts (MEFs) suggest that the ATXN7L3-related DUB activity regulates only a subset of genes in both cell types. However, the gene sets and the extent of their deregulation were different in mESCs and MEFs. Interestingly, the strong increase of H2Bub1 levels observed in the Atxn7l3(-/-) mESCs, or Atxn7l3(-/-) MEFs, does not correlate with the modest changes in RNA Polymerase II (Pol II) occupancy and lack of changes in Pol II elongation observed in the two Atxn7l3(-/-) cellular systems. These observations together indicate that deubiquitylation of histone H2Bub1 does not directly regulate global Pol II transcription elongation (Wang, 2021).

Molecular and electrophysiological features of spinocerebellar ataxia type seven in induced pluripotent stem cells

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the ATXN7 gene. Patients with this disease suffer from a degeneration of their cerebellar Purkinje neurons and retinal photoreceptors that result in a progressive ataxia and loss of vision. As with many neurodegenerative diseases, studies of pathogenesis have been hindered by a lack of disease-relevant models. To this end, this study generated induced pluripotent stem cells (iPSCs) from a cohort of SCA7 patients in South Africa. First, the SCA7 affected iPSCs differentiated into neurons which showed evidence of a transcriptional phenotype affecting components of STAGA (ATXN7 and KAT2A) and the heat shock protein pathway (DNAJA1 and HSP70). Electrophysiology was performed on the SCA7 iPSC-derived neurons; these cells showed features of functional aberrations. Lastly, it was possible to differentiate the SCA7 iPSCs into retinal photoreceptors that also showed similar transcriptional aberrations to the SCA7 neurons. These findings give technical insights on how iPSC-derived neurons and photoreceptors can be derived from SCA7 patients and demonstrate that these cells express molecular and electrophysiological differences that may be indicative of impaired neuronal health. It is hoped that these findings will contribute towards the ongoing efforts to establish the cell-derived models of neurodegenerative diseases that are needed to develop patient-specific treatments (Burman, 2021).

Polyglutamine expanded Ataxin-7 induces DNA damage and alters FUS localization and function

Polyglutamine (polyQ) diseases, such as Spinocerebellar ataxia type 7 (SCA7), are caused by expansions of polyQ repeats in disease specific proteins. The sequestration of vital proteins into aggregates formed by polyQ proteins is believed to be a common pathological mechanism in these disorders. The RNA-binding protein FUS has been observed in polyQ aggregates, though if disruption of this protein plays a role in the neuronal dysfunction in SCA7 or other polyQ diseases remains unclear. This study therefore analysed FUS localisation and function in a stable inducible PC12 cell model expressing the SCA7 polyQ protein ATXN7. There was a high degree of FUS sequestration, which was associated with a more cytoplasmic FUS localisation, as well as a decreased expression of FUS regulated mRNAs. In contrast, the role of FUS in the formation of gammaH2AX positive DNA damage foci was unaffected. In fact, a statistical increase in the number of gammaH2AX foci, as well as an increased trend of single and double strand DNA breaks, detected by comet assay, could be observed in mutant ATXN7 cells. These results were further corroborated by a clear trend towards increased DNA damage in SCA7 patient fibroblasts. These findings suggest that both alterations in the RNA regulatory functions of FUS, and increased DNA damage, may contribute to the pathology of SCA7 (Niss, 2021).

Ataxin-7 associates with microtubules and stabilizes the cytoskeletal network

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. This study defined 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 (Nakamura, 2012).

Search PubMed for articles about Drosophila Ataxin-7

Burman, R. J., Watson, L. M., Smith, D. C., Raimondo, J. V., Ballo, R., Scholefield, J., Cowley, S. A., Wood, M. J. A., Kidson, S. H. and Greenberg, L. J. (2021). Molecular and electrophysiological features of spinocerebellar ataxia type seven in induced pluripotent stem cells. PLoS One 16(2): e0247434. PubMed ID: 33626063

Cloud, V., Thapa, A., Morales-Sosa, P., Miller, T. M., Miller, S. A., Holsapple, D., Gerhart, P. M., Momtahan, E., Jack, J. L., Leiva, E., Rapp, S. R., Shelton, L. G., Pierce, R. A., Martin-Brown, S., Florens, L., Washburn, M. P. and Mohan, R. D. (2019). Ataxin-7 and Non-stop coordinate SCAR protein levels, subcellular localization, and actin cytoskeleton organization. Elife 8. PubMed ID: 31348003

Latouche, M., Lasbleiz, C., Martin, E., Monnier, V., Debeir, T., Mouatt-Prigent, A., Muriel, M. P., Morel, L., Ruberg, M., Brice, A., Stevanin, G. and Tricoire, H. (2007). A conditional pan-neuronal Drosophila model of spinocerebellar ataxia 7 with a reversible adult phenotype suitable for identifying modifier genes. J Neurosci 27(10): 2483-2492. PubMed ID: 17344386

Mohan, R. D., Dialynas, G., Weake, V. M., Liu, J., Martin-Brown, S., Florens, L., Washburn, M. P., Workman, J. L. and Abmayr, S. M. (2014). Loss of Drosophila Ataxin-7, a SAGA subunit, reduces H2B ubiquitination and leads to neural and retinal degeneration. Genes Dev 28(3): 259-272. PubMed ID: 24493646

Nakamura, Y., Tagawa, K., Oka, T., Sasabe, T., Ito, H., Shiwaku, H., La Spada, A. R. and Okazawa, H. (2012). Ataxin-7 associates with microtubules and stabilizes the cytoskeletal network. Hum Mol Genet 21(5): 1099-1110. PubMed ID: 22100762

Niewiadomska-Cimicka, A., Doussau, F., Perot, J. B., Roux, M. J., Keime, C., Hache, A., Piguet, F., Novati, A., Weber, C., Yalcin, B., Meziane, H., Champy, M. F., Grandgirard, E., Karam, A., Messaddeq, N., Eisenmann, A., Brouillet, E., Nguyen, H. H. P., Flament, J., Isope, P. and Trottier, Y. (2021). SCA7 Mouse Cerebellar Pathology Reveals Preferential Downregulation of Key Purkinje Cell-Identity Genes and Shared Disease Signature with SCA1 and SCA2. J Neurosci 41(22): 4910-4936. PubMed ID: 33888607

Niss, F., Zaidi, W., Hallberg, E. and Strom, A. L. (2021). Polyglutamine expanded Ataxin-7 induces DNA damage and alters FUS localization and function. Mol Cell Neurosci 110: 103584. PubMed ID: 33338633

Vinatier, G., Corsi, J. M., Mignotte, B. and Gaumer, S. (2015). Quantification of Ataxin-3 and Ataxin-7 aggregates formed in vivo in Drosophila reveals a threshold of aggregated polyglutamine proteins associated with cellular toxicity. Biochem Biophys Res Commun 464(4): 1060-1065. PubMed ID: 26210447

Wang, F., El-Saafin, F., Ye, T., Stierle, M., Negroni, L., Durik, M., Fischer, V., Devys, D., Vincent, S. D. and Tora, L. (2021). Histone H2Bub1 deubiquitylation is essential for mouse development, but does not regulate global RNA polymerase II transcription. Cell Death Differ 28(8): 2385-2403. PubMed ID: 33731875

date revised: 2 February 2022

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