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Article ; Online: Deregulation of autophagy in postmortem brains of Machado-Joseph disease patients.

Sittler, Annie / Muriel, Marie-Paule / Marinello, Martina / Brice, Alexis / den Dunnen, Wilfred / Alves, Sandro

Neuropathology : official journal of the Japanese Society of Neuropathology

2017 Volume 38, Issue 2, Page(s) 113–124

Abstract: Autophagy, the major pathway for protein turnover, is critical to maintain cellular homeostasis and has been implicated in neurodegenerative diseases. The aim of this research was to analyze the expression of autophagy markers in postmortem brains from ... ...

Abstract	Autophagy, the major pathway for protein turnover, is critical to maintain cellular homeostasis and has been implicated in neurodegenerative diseases. The aim of this research was to analyze the expression of autophagy markers in postmortem brains from Machado-Joseph disease (MJD) patients. The expression of autophagy markers in the cerebellum and the oculomotor nucleus from MJD patients and age-matched controls with no signs of neuropathology was inspected postmortem by immunohistochemistry (IHC) and Western blot. Furthermore, autophagy was examined by means of transmission electron microscopy (TEM). Western blot and IHC revealed nuclear accumulation of misfolded ataxin-3 (ATXN3) and the presence of ubiquitin- and p62-positive aggregates in MJD patients as compared to controls. Moreover, the autophagic proteins, autophagy-related gene (Atg) protein (ATG)-7, ATG-12, ATG16L2 and autophagosomal microtubule-associated protein light chain 3 (LC3) were significantly increased in MJD brains relative to controls, while beclin-1 levels were reduced in MJD patients. Increase in the levels of lysosomal-associated membrane protein 2 (LAMP-2) and of the endosomal markers (Rab7 and Rab1A) were observed in MJD patients relatively to controls. In addition, these findings were further confirmed by TEM in brain tissue where large vesicles accumulating electron-dense materials were highly enriched in MJD patients. Postmortem brains with MJD exhibit increased markers of autophagy relative to age-matched control brains, therefore suggesting strong dysregulation of autophagy that may have an important role in the course of MJD pathogenesis.
MeSH term(s)	Adult ; Ataxin-3/metabolism ; Autophagy ; Beclin-1/metabolism ; Biomarkers/metabolism ; Cell Adhesion Molecules, Neuronal/metabolism ; Cerebellum/metabolism ; Endosomes/metabolism ; Female ; GPI-Linked Proteins/metabolism ; Humans ; Lysosomes/metabolism ; Machado-Joseph Disease/metabolism ; Male ; Microtubule-Associated Proteins/metabolism ; Middle Aged ; Oculomotor Nuclear Complex/metabolism ; Proto-Oncogene Proteins c-myc/metabolism ; Sirolimus/metabolism ; Ubiquitin/metabolism
Chemical Substances	Beclin-1 ; Biomarkers ; Cell Adhesion Molecules, Neuronal ; GPI-Linked Proteins ; MAP1LC3A protein, human ; Microtubule-Associated Proteins ; Proto-Oncogene Proteins c-myc ; Ubiquitin ; limbic system-associated membrane protein ; Ataxin-3 (EC 3.4.19.12) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2017-12-08
Publishing country	Australia
Document type	Journal Article
ZDB-ID	1483794-8
ISSN	1440-1789 ; 0919-6544
ISSN (online)	1440-1789
ISSN	0919-6544
DOI	10.1111/neup.12433
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Article ; Online: SUMOylation by SUMO2 is implicated in the degradation of misfolded ataxin-7 via RNF4 in SCA7 models.

Marinello, Martina / Werner, Andreas / Giannone, Mariagiovanna / Tahiri, Khadija / Alves, Sandro / Tesson, Christelle / den Dunnen, Wilfred / Seeler, Jacob-S / Brice, Alexis / Sittler, Annie

Disease models & mechanisms

2019 Volume 12, Issue 1

Abstract: Perturbation of protein homeostasis and aggregation of misfolded proteins is a major cause of many human diseases. A hallmark of the neurodegenerative disease spinocerebellar ataxia type 7 (SCA7) is the intranuclear accumulation of mutant, misfolded ... ...

Abstract	Perturbation of protein homeostasis and aggregation of misfolded proteins is a major cause of many human diseases. A hallmark of the neurodegenerative disease spinocerebellar ataxia type 7 (SCA7) is the intranuclear accumulation of mutant, misfolded ataxin-7 (polyQ-ATXN7). Here, we show that endogenous ATXN7 is modified by SUMO proteins, thus also suggesting a physiological role for this modification under conditions of proteotoxic stress caused by the accumulation of polyQ-ATXN7. Co-immunoprecipitation experiments, immunofluorescence microscopy and proximity ligation assays confirmed the colocalization and interaction of polyQ-ATXN7 with SUMO2 in cells. Moreover, upon inhibition of the proteasome, both endogenous SUMO2/3 and the RNF4 ubiquitin ligase surround large polyQ-ATXN7 intranuclear inclusions. Overexpression of RNF4 and/or SUMO2 significantly decreased levels of polyQ-ATXN7 and, upon proteasomal inhibition, led to a marked increase in the polyubiquitination of polyQ-ATXN7. This provides a mechanism for the clearance of polyQ-ATXN7 from affected cells that involves the recruitment of RNF4 by SUMO2/3-modified polyQ-ATXN7, thus leading to its ubiquitination and proteasomal degradation. In a SCA7 knock-in mouse model, we similarly observed colocalization of SUMO2/3 with polyQ-ATXN7 inclusions in the cerebellum and retina. Furthermore, we detected accumulation of SUMO2/3 high-molecular-mass species in the cerebellum of SCA7 knock-in mice, compared with their wild-type littermates, and changes in SUMO-related transcripts. Immunohistochemical analysis showed the accumulation of SUMO proteins and RNF4 in the cerebellum of SCA7 patients. Taken together, our results show that the SUMO pathway contributes to the clearance of aggregated ATXN7 and suggest that its deregulation might be associated with SCA7 disease progression.
MeSH term(s)	Animals ; Ataxin-7/metabolism ; Cerebellum/metabolism ; Child ; Disease Models, Animal ; HEK293 Cells ; HeLa Cells ; Humans ; Inclusion Bodies/metabolism ; MCF-7 Cells ; Mice ; Middle Aged ; Mutation/genetics ; Nuclear Proteins/metabolism ; Promyelocytic Leukemia Protein/metabolism ; Proteasome Inhibitors/pharmacology ; Protein Aggregates/drug effects ; Protein Folding/drug effects ; Proteolysis/drug effects ; Small Ubiquitin-Related Modifier Proteins/metabolism ; Spinocerebellar Ataxias/metabolism ; Spinocerebellar Ataxias/pathology ; Sumoylation/drug effects ; Transcription Factors/metabolism ; Ubiquitin/metabolism
Chemical Substances	Ataxin-7 ; Nuclear Proteins ; Promyelocytic Leukemia Protein ; Proteasome Inhibitors ; Protein Aggregates ; RNF4 protein, human ; SUMO2 protein, human ; Small Ubiquitin-Related Modifier Proteins ; Transcription Factors ; Ubiquitin ; PML protein, human (143220-95-5)
Language	English
Publishing date	2019-01-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1754-8411
ISSN (online)	1754-8411
DOI	10.1242/dmm.036145
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Article ; Online: Control of Huntington's Disease-Associated Phenotypes by the Striatum-Enriched Transcription Factor Foxp2.

Hachigian, Lea J / Carmona, Vitor / Fenster, Robert J / Kulicke, Ruth / Heilbut, Adrian / Sittler, Annie / Pereira de Almeida, Luís / Mesirov, Jill P / Gao, Fan / Kolaczyk, Eric D / Heiman, Myriam

Cell reports

2017 Volume 21, Issue 10, Page(s) 2688–2695

Abstract: Alteration of corticostriatal glutamatergic function is an early pathophysiological change associated with Huntington's disease (HD). The factors that regulate the maintenance of corticostriatal glutamatergic synapses post-developmentally are not well ... ...

Abstract	Alteration of corticostriatal glutamatergic function is an early pathophysiological change associated with Huntington's disease (HD). The factors that regulate the maintenance of corticostriatal glutamatergic synapses post-developmentally are not well understood. Recently, the striatum-enriched transcription factor Foxp2 was implicated in the development of these synapses. Here, we show that, in mice, overexpression of Foxp2 in the adult striatum of two models of HD leads to rescue of HD-associated behaviors, while knockdown of Foxp2 in wild-type mice leads to development of HD-associated behaviors. We note that Foxp2 encodes the longest polyglutamine repeat protein in the human reference genome, and we show that it can be sequestered into aggregates with polyglutamine-expanded mutant Huntingtin protein (mHTT). Foxp2 overexpression in HD model mice leads to altered expression of several genes associated with synaptic function, genes that present additional targets for normalization of corticostriatal dysfunction in HD.
MeSH term(s)	Animals ; Blotting, Western ; Corpus Striatum/metabolism ; Disease Models, Animal ; Fluorescent Antibody Technique, Indirect ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; Gene Expression Regulation/genetics ; Gene Expression Regulation/physiology ; Humans ; Huntington Disease/genetics ; Huntington Disease/metabolism ; Male ; Mice ; Phenotype ; Repressor Proteins/genetics ; Repressor Proteins/metabolism
Chemical Substances	Forkhead Transcription Factors ; Foxp2 protein, mouse ; Repressor Proteins
Language	English
Publishing date	2017-12-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2017.11.018
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Article ; Online: Lentiviral vector-mediated overexpression of mutant ataxin-7 recapitulates SCA7 pathology and promotes accumulation of the FUS/TLS and MBNL1 RNA-binding proteins.

Alves, Sandro / Marais, Thibaut / Biferi, Maria-Grazia / Furling, Denis / Marinello, Martina / El Hachimi, Khalid / Cartier, Nathalie / Ruberg, Merle / Stevanin, Giovanni / Brice, Alexis / Barkats, Martine / Sittler, Annie

Molecular neurodegeneration

2016 Volume 11, Issue 1, Page(s) 58

Abstract: Background: We used lentiviral vectors (LVs) to generate a new SCA7 animal model overexpressing a truncated mutant ataxin-7 (MUT ATXN7) fragment in the mouse cerebellum, in order to characterize the specific neuropathological and behavioral consequences ...

Abstract	Background: We used lentiviral vectors (LVs) to generate a new SCA7 animal model overexpressing a truncated mutant ataxin-7 (MUT ATXN7) fragment in the mouse cerebellum, in order to characterize the specific neuropathological and behavioral consequences of the genetic defect in this brain structure. Results: LV-mediated overexpression of MUT ATXN7 into the cerebellum of C57/BL6 adult mice induced neuropathological features similar to that observed in patients, such as intranuclear aggregates in Purkinje cells (PC), loss of synaptic markers, neuroinflammation, and neuronal death. No neuropathological changes were observed when truncated wild-type ataxin-7 (WT ATXN7) was injected. Interestingly, the local delivery of LV-expressing mutant ataxin-7 (LV-MUT-ATXN7) into the cerebellum of wild-type mice also mediated the development of an ataxic phenotype at 8 to 12 weeks post-injection. Importantly, our data revealed abnormal levels of the FUS/TLS, MBNL1, and TDP-43 RNA-binding proteins in the cerebellum of the LV-MUT-ATXN7 injected mice. MUT ATXN7 overexpression induced an increase in the levels of the pathological phosphorylated TDP-43, and a decrease in the levels of soluble FUS/TLS, with both proteins accumulating within ATXN7-positive intranuclear inclusions. MBNL1 also co-aggregated with MUT ATXN7 in most PC nuclear inclusions. Interestingly, no MBNL2 aggregation was observed in cerebellar MUT ATXN7 aggregates. Immunohistochemical studies in postmortem tissue from SCA7 patients and SCA7 knock-in mice confirmed SCA7-induced nuclear accumulation of FUS/TLS and MBNL1, strongly suggesting that these proteins play a physiopathological role in SCA7. Conclusions: This study validates a novel SCA7 mouse model based on lentiviral vectors, in which strong and sustained expression of MUT ATXN7 in the cerebellum was found sufficient to generate motor defects.
MeSH term(s)	Animals ; Ataxin-7/genetics ; Ataxin-7/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Disease Models, Animal ; Female ; Humans ; Lentivirus/genetics ; Mice, Inbred C57BL ; Neurons/metabolism ; Phenotype ; RNA-Binding Proteins/metabolism ; Spinocerebellar Ataxias/genetics
Chemical Substances	Ataxin-7 ; DNA-Binding Proteins ; MBNL1 protein, human ; Mbnl1 protein, mouse ; RNA-Binding Proteins
Language	English
Publishing date	2016-07-28
Publishing country	England
Document type	Journal Article
ISSN	1750-1326
ISSN (online)	1750-1326
DOI	10.1186/s13024-016-0123-2
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Article ; Online: Interferon β induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice.

Chort, Alice / Alves, Sandro / Marinello, Martina / Dufresnois, Béatrice / Dornbierer, Jean-Gabriel / Tesson, Christelle / Latouche, Morwena / Baker, Darren P / Barkats, Martine / El Hachimi, Khalid H / Ruberg, Merle / Janer, Alexandre / Stevanin, Giovanni / Brice, Alexis / Sittler, Annie

Brain : a journal of neurology

2013 Volume 136, Issue Pt 6, Page(s) 1732–1745

Abstract: We showed previously, in a cell model of spinocerebellar ataxia 7, that interferon beta induces the expression of PML protein and the formation of PML protein nuclear bodies that degrade mutant ataxin 7, suggesting that the cytokine, used to treat ... ...

Abstract	We showed previously, in a cell model of spinocerebellar ataxia 7, that interferon beta induces the expression of PML protein and the formation of PML protein nuclear bodies that degrade mutant ataxin 7, suggesting that the cytokine, used to treat multiple sclerosis, might have therapeutic value in spinocerebellar ataxia 7. We now show that interferon beta also induces PML-dependent clearance of ataxin 7 in a preclinical model, SCA7(266Q/5Q) knock-in mice, and improves motor function. Interestingly, the presence of mutant ataxin 7 in the mice induces itself the expression of endogenous interferon beta and its receptor. Immunohistological studies in brains from two patients with spinocerebellar ataxia 7 confirmed that these modifications are also caused by the disease in humans. Interferon beta, administered intraperitoneally three times a week in the knock-in mice, was internalized with its receptor in Purkinje and other cells and translocated to the nucleus. The treatment induced PML protein expression and the formation of PML protein nuclear bodies and decreased mutant ataxin 7 in neuronal intranuclear inclusions, the hallmark of the disease. No reactive gliosis or other signs of toxicity were observed in the brain or internal organs. The performance of the SCA7(266Q/5Q) knock-in mice was significantly improved on two behavioural tests sensitive to cerebellar function: the Locotronic® Test of locomotor function and the Beam Walking Test of balance, motor coordination and fine movements, which are affected in patients with spinocerebellar ataxia 7. In addition to motor dysfunction, SCA7(266Q/5Q) mice present abnormalities in the retina as in patients: ataxin 7-positive neuronal intranuclear inclusions that were reduced by interferon beta treatment. Finally, since neuronal death does not occur in the cerebellum of SCA7(266Q/5Q) mice, we showed in primary cell cultures expressing mutant ataxin 7 that interferon beta treatment improves Purkinje cell survival.
MeSH term(s)	Adult ; Aged ; Animals ; Ataxin-7 ; Cells, Cultured ; Child ; Gene Knock-In Techniques ; Humans ; Interferon-beta/therapeutic use ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Activity/genetics ; Mutation/genetics ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Rats ; Rats, Wistar ; Spinocerebellar Ataxias/drug therapy ; Spinocerebellar Ataxias/genetics ; Spinocerebellar Ataxias/physiopathology
Chemical Substances	ATXN7 protein, human ; Ataxin-7 ; Atxn7 protein, mouse ; Atxn7 protein, rat ; Nerve Tissue Proteins ; Interferon-beta (77238-31-4)
Language	English
Publishing date	2013-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awt061
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Article: Polyglutamine and polyalanine expansions in ataxin7 result in different types of aggregation and levels of toxicity.

Latouche, Morwena / Fragner, Pascal / Martin, Elodie / El Hachimi, Khalid H / Zander, Cecilia / Sittler, Annie / Ruberg, Merle / Brice, Alexis / Stevanin, Giovanni

Molecular and cellular neurosciences

2006 Volume 31, Issue 3, Page(s) 438–445

Abstract: Spinocerebellar ataxia type 7 (SCA7) is caused by expansion of a (CAG)n repeat in the ataxin7 gene, resulting in an abnormally long polyglutamine polyQ tract in the translated protein that aggregates in the form of neuronal intranuclear inclusions. ... ...

Abstract	Spinocerebellar ataxia type 7 (SCA7) is caused by expansion of a (CAG)n repeat in the ataxin7 gene, resulting in an abnormally long polyglutamine polyQ tract in the translated protein that aggregates in the form of neuronal intranuclear inclusions. Polyalanine (polyA) stretches, implicated in several genetic disorders, also appear to aggregate. To investigate the role of the aggregates in the pathologies, we compared the effects of ataxin7 containing a polyA (ataxin7 - 90A) or polyQ (ataxin7 - 100Q) expansion in HEK 293 cells and in primary cultures of rat mesencephalon. Both proteins formed nuclear and perinuclear aggregates that contained molecular chaperones and components of the ubiquitin-proteasome system, suggesting that they were abnormally folded. Ataxin-90A aggregates differed morphologically from ataxin7 - 100Q aggregates, consisted of small and amorphous rather than fibrillar inclusions and were more toxic to mesencephalic neurons, suggesting that toxicity was determined by the type of aggregate rather than the cellular misfolding response.
MeSH term(s)	Animals ; Ataxin-7 ; Brain/metabolism ; Brain/pathology ; Brain/physiopathology ; Cell Line ; Cells, Cultured ; Humans ; Intranuclear Inclusion Bodies/genetics ; Intranuclear Inclusion Bodies/metabolism ; Intranuclear Inclusion Bodies/pathology ; Molecular Chaperones/genetics ; Molecular Chaperones/metabolism ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Nerve Tissue Proteins/toxicity ; Neurofibrils/genetics ; Neurofibrils/metabolism ; Neurofibrils/pathology ; Neurons/metabolism ; Neurons/pathology ; Peptides/metabolism ; Proteasome Endopeptidase Complex/genetics ; Proteasome Endopeptidase Complex/metabolism ; Protein Folding ; Rats ; Spinocerebellar Ataxias/genetics ; Spinocerebellar Ataxias/metabolism ; Spinocerebellar Ataxias/physiopathology
Chemical Substances	ATXN7 protein, human ; Ataxin-7 ; Atxn7 protein, rat ; Molecular Chaperones ; Nerve Tissue Proteins ; Peptides ; polyalanine (25191-17-7) ; polyglutamine (26700-71-0) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2006-03
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1046640-x
ISSN	1095-9327 ; 1044-7431
ISSN (online)	1095-9327
ISSN	1044-7431
DOI	10.1016/j.mcn.2005.10.013
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Article: PML clastosomes prevent nuclear accumulation of mutant ataxin-7 and other polyglutamine proteins.

Janer, Alexandre / Martin, Elodie / Muriel, Marie-Paule / Latouche, Morwena / Fujigasaki, Hiroto / Ruberg, Merle / Brice, Alexis / Trottier, Yvon / Sittler, Annie

The Journal of cell biology

2006 Volume 174, Issue 1, Page(s) 65–76

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Ataxin-7 ; COS Cells ; Cadmium Chloride/pharmacology ; Cell Nucleus/metabolism ; Cells, Cultured ; Cercopithecus aethiops ; Humans ; Interferon-beta/pharmacology ; Mice ; Mice, Transgenic ; Multiprotein Complexes/drug effects ; Multiprotein Complexes/metabolism ; Mutation ; Neoplasm Proteins/drug effects ; Neoplasm Proteins/metabolism ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Nuclear Proteins/drug effects ; Nuclear Proteins/metabolism ; Peptides/genetics ; Promyelocytic Leukemia Protein ; Proteasome Endopeptidase Complex/drug effects ; Proteasome Endopeptidase Complex/metabolism ; Protein Isoforms/drug effects ; Protein Isoforms/metabolism ; Transcription Factors/drug effects ; Transcription Factors/metabolism ; Tumor Suppressor Proteins/drug effects ; Tumor Suppressor Proteins/metabolism
Chemical Substances	ATXN7 protein, human ; Ataxin-7 ; Atxn7 protein, mouse ; Multiprotein Complexes ; Neoplasm Proteins ; Nerve Tissue Proteins ; Nuclear Proteins ; Peptides ; Pml protein, mouse ; Promyelocytic Leukemia Protein ; Protein Isoforms ; Transcription Factors ; Tumor Suppressor Proteins ; PML protein, human (143220-95-5) ; polyglutamine (26700-71-0) ; Interferon-beta (77238-31-4) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Cadmium Chloride (J6K4F9V3BA)
Language	English
Publishing date	2006-07-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.200511045
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Article ; Online: Corrigendum: Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7.

Tan, Jennifer Y / Vance, Keith W / Varela, Miguel A / Sirey, Tamara / Watson, Lauren M / Curtis, Helen J / Marinello, Martina / Alves, Sandro / Steinkraus, Bruno R / Cooper, Sarah / Nesterova, Tatyana / Brockdorff, Neil / Fulga, Tudor A / Brice, Alexis / Sittler, Annie / Oliver, Peter L / Wood, Matthew J / Ponting, Chris P / Marques, Ana C

Nature structural & molecular biology

2015 Volume 22, Issue 3, Page(s) 272

Language	English
Publishing date	2015-03
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/nsmb0315-272b
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Article ; Online: SUMOylation attenuates the aggregation propensity and cellular toxicity of the polyglutamine expanded ataxin-7.

Janer, Alexandre / Werner, Andreas / Takahashi-Fujigasaki, Junko / Daret, Aurélie / Fujigasaki, Hiroto / Takada, Koji / Duyckaerts, Charles / Brice, Alexis / Dejean, Anne / Sittler, Annie

Human molecular genetics

2010 Volume 19, Issue 1, Page(s) 181–195

Abstract: Post-translational modification by SUMO (small ubiquitin-like modifier) was proposed to modulate the pathogenesis of several neurodegenerative diseases. Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder, whose pathology is caused by an ...

Abstract	Post-translational modification by SUMO (small ubiquitin-like modifier) was proposed to modulate the pathogenesis of several neurodegenerative diseases. Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder, whose pathology is caused by an expansion of a polyglutamine stretch in the protein ataxin-7 (ATXN7). Here, we identified ATXN7 as new target for SUMOylation in vitro and in vivo. The major SUMO acceptor site was mapped to lysine 257, which is part of an evolutionarily conserved consensus SUMOylation motif. SUMOylation did not influence the subcellular localization of ATXN7 nor its interaction with components of the TFTC/STAGA complex. Expansion of the polyglutamine stretch did not impair the SUMOylation of ATXN7. Furthermore, SUMO1 and SUMO2 colocalized with ATXN7 in a subset of neuronal intranuclear inclusions in the brain of SCA7 patients and SCA7 knock-in mice. In a COS-7 cellular model of SCA7, in addition to diffuse nucleoplasmic staining we identified two populations of nuclear inclusions: homogenous or non-homogenous. Non-homogenous inclusions showed significantly reduced colocalization with SUMO1 and SUMO2, but were highly enriched in Hsp70, 19S proteasome and ubiquitin. Interestingly, they were characterized by increased staining with the apoptotic marker caspase-3 and by disruption of PML nuclear bodies. Importantly, preventing the SUMOylation of expanded ATXN7 by mutating the SUMO site increased both the amount of SDS-insoluble aggregates and of caspase-3 positive non-homogenous inclusions, which act toxic to the cells. Our results demonstrate an influence of SUMOylation on the multistep aggregation process of ATXN7 and implicate a role for ATXN7 SUMOylation in SCA7 pathogenesis.
MeSH term(s)	Adult ; Animals ; Ataxin-7 ; Caspase 3/metabolism ; Child ; Enzyme Activation/drug effects ; Fatal Outcome ; Female ; Humans ; Intranuclear Inclusion Bodies/drug effects ; Intranuclear Inclusion Bodies/metabolism ; Lysine/metabolism ; Male ; Mice ; Multiprotein Complexes/metabolism ; Nerve Tissue Proteins/chemistry ; Nerve Tissue Proteins/toxicity ; Neurons/drug effects ; Neurons/metabolism ; Peptides/toxicity ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding/drug effects ; Protein Structure, Quaternary ; Protein Transport/drug effects ; Small Ubiquitin-Related Modifier Proteins/metabolism ; Spinocerebellar Ataxias/metabolism ; Spinocerebellar Ataxias/pathology ; Subcellular Fractions/drug effects ; Subcellular Fractions/metabolism ; Trinucleotide Repeat Expansion/genetics ; Ubiquitin/metabolism
Chemical Substances	ATXN7 protein, human ; Ataxin-7 ; Atxn7 protein, mouse ; Multiprotein Complexes ; Nerve Tissue Proteins ; Peptides ; Small Ubiquitin-Related Modifier Proteins ; Ubiquitin ; polyglutamine (26700-71-0) ; Caspase 3 (EC 3.4.22.-) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2010-01-01
Publishing country	England
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddp478
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Article: PML clastosomes prevent nuclear accumulation of mutant ataxin-7 and other polyglutamine proteins

Janer, Alexandre / Martin, Elodie / Muriel, Marie-Paule / Latouche, Morwena / Fujigasaki, Hiroto / Ruberg, Merle / Brice, Alexis / Trottier, Yvon / Sittler, Annie

Journal of cell biology. 2006 July 3, v. 174, no. 1

2006

Abstract	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, β-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.
Language	English
Dates of publication	2006-0703
Size	p. 65-76.
Publishing place	The Rockefeller University Press
Document type	Article
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
Database	NAL-Catalogue (AGRICOLA)

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