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Huda Y. Zoghbi - One of the best experts on this subject based on the ideXlab platform.
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exercise and genetic rescue of sca1 via the transcriptional repressor capicua
Science, 2011Co-Authors: John D Fryer, Chad A. Shaw, Peng Yu, Hyojin Kang, Caleigh Mandelbrehm, Angela N Carter, Juan Crespobarreto, Adriano Flora, Huda Y. ZoghbiAbstract:Spinocerebellar Ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by expansion of a translated CAG repeat in Ataxin-1 (ATXN1). To determine the long-term effects of exercise, we implemented a mild exercise regimen in a mouse model of SCA1 and found a considerable improvement in survival accompanied by up-regulation of epidermal growth factor and consequential down-regulation of Capicua, which is an ATXN1 interactor. Offspring of Capicua mutant mice bred to SCA1 mice showed significant improvement of all disease phenotypes. Although polyglutamine-expanded Atxn1 caused some loss of Capicua function, further reduction of Capicua levels—either genetically or by exercise—mitigated the disease phenotypes by dampening the toxic gain of function. Thus, exercise might have long-term beneficial effects in other Ataxias and neurodegenerative diseases.
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Comparison of an expanded Ataxia interactome with patient medical records reveals a relationship between macular degeneration and Ataxia
Human molecular genetics, 2010Co-Authors: Juliette J. Kahle, David E. Hill, Natali Gulbahce, Chad A. Shaw, Janghoo Lim, Albert-lászló Barabási, Huda Y. ZoghbiAbstract:Spinocerebellar Ataxias 6 and 7 (SCA6 and SCA7) are neurodegenerative disorders caused by expansion of CAG repeats encoding polyglutamine (polyQ) tracts in CACNA1A, the alpha1A subunit of the P/Q-type calcium channel, and ataxin-7 (ATXN7), a component of a chromatin-remodeling complex, respectively. We hypothesized that finding new protein partners for ATXN7 and CACNA1A would provide insight into the biology of their respective diseases and their relationship to other Ataxia-causing proteins. We identified 118 protein interactions for CACNA1A and ATXN7 linking them to other Ataxia-causing proteins and the Ataxia network. To begin to understand the biological relevance of these protein interactions within the Ataxia network, we used OMIM to identify diseases associated with the expanded Ataxia network. We then used Medicare patient records to determine if any of these diseases co-occur with hereditary Ataxia. We found that patients with Ataxia are at 3.03-fold greater risk of these diseases than Medicare patients overall. One of the diseases comorbid with Ataxia is macular degeneration (MD). The Ataxia network is significantly (P= 7.37 × 10(-5)) enriched for proteins that interact with known MD-causing proteins, forming a MD subnetwork. We found that at least two of the proteins in the MD subnetwork have altered expression in the retina of Ataxin-7(266Q/+) mice suggesting an in vivo functional relationship with ATXN7. Together these data reveal novel protein interactions and suggest potential pathways that can contribute to the pathophysiology of Ataxia, MD, and diseases comorbid with Ataxia.
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SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity.
Neuron, 2003Co-Authors: Seung-yun Yoo, Shiming Chen, Mark E. Pennesi, Edwin J. Weeber, Richard Atkinson, Dawna L. Armstrong, J. David Sweatt, Huda Y. ZoghbiAbstract:We targeted 266 CAG repeats (a number that causes infantile-onset disease) into the mouse Sca7 locus to generate an authentic model of spinocerebellar Ataxia type 7 (SCA7). These mice reproduced features of infantile SCA7 (Ataxia, visual impairments, and premature death) and showed impaired short-term synaptic potentiation; downregulation of photoreceptor-specific genes, despite apparently normal CRX activity, led to shortening of photoreceptor outer segments. Wild-type ataxin-7 was barely detectable, as was mutant ataxin-7 in young animals; with increasing age, however, ataxin-7 staining became more pronounced. Neurons that appeared most vulnerable had relatively high levels of mutant ataxin-7; it is interesting, however, that marked dysfunction occurred in these neurons weeks prior to the appearance of nuclear inclusions. These data demonstrate that glutamine expansion stabilizes mutant ataxin-7, provide an explanation for selective neuronal vulnerability, and show that mutant ataxin-7 impairs posttetanic potentiation (PTP).
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Amino acids in a region of ataxin-1 outside of the polyglutamine tract influence the course of disease in SCA1 transgenic mice
NeuroMolecular Medicine, 2002Co-Authors: Pamela J. Skinner, Cynthia A. Vierra-green, Effat Emamian, Huda Y. ZoghbiAbstract:Spinocerebellar Ataxia type 1 (SCA1) belongs to a family of polyglutamine induced neurodegenerative disorders. Transgenic mice that overexpress a mutant allele of the SCA1 gene develop a progressive Ataxia and Purkinje cell pathology. In this report, the pathological importance of a segment of ataxin-1 previously shown to be important for protein-protein interactions was examined. While the absence of a 122 amino acid segment from the protein-protein interaction region of ataxin-1 did not effect the initiation of disease, its absence substantially suppressed the progression of disease in SCA1 transgenic mice. Thus, these data suggest that this region of ataxin-1 has a role in disease progression. Furthermore, these results provide evidence that ataxin-1-induced disease initiation and disease progression involve distinct molecular events.
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ataxin 1 nuclear localization and aggregation role in polyglutamine induced disease in sca1 transgenic mice
Cell, 1998Co-Authors: Ivan A Klement, Michael D Kaytor, Pamela J. Skinner, Hong Yi, Steven M Hersch, Brent H Clark, Huda Y. ZoghbiAbstract:Abstract Transgenic mice carrying the spinocerebellar Ataxia type 1 (SCA1) gene, a polyglutamine neurodegenerative disorder, develop Ataxia with ataxin-1 localized to aggregates within cerebellar Purkinje cells nuclei. To examine the importance of nuclear localization and aggregation in pathogenesis, mice expressing ataxin-1[82] with a mutated NLS were established. These mice did not develop disease, demonstrating that nuclear localization is critical for pathogenesis. In a second series of transgenic mice, ataxin-1[77] containing a deletion within the self-association region was expressed within Purkinje cells nuclei. These mice developed Ataxia and Purkinje cell pathology similar to the original SCA1 mice. However, no evidence of nuclear ataxin-1 aggregates was found. Thus, although nuclear localization of ataxin-1 is necessary, nuclear aggregation of ataxin-1 is not required to initiate pathogenesis in transgenic mice.
Guy A. Rouleau - One of the best experts on this subject based on the ideXlab platform.
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heterozygous missense pathogenic variants within the second spectrin repeat of sptbn2 lead to infantile onset cerebellar Ataxia
Journal of Child Neurology, 2020Co-Authors: Guy A. Rouleau, Andrea Accogli, Judith Stonge, Nassima Addourboudrahem, Joel Lafondlapalme, Alexandre D Laporte, Jeanbaptiste Riviere, Myriam SrourAbstract:The term spinocerebellar Ataxia encompasses a heterogeneous group of neurodegenerative disorders due to pathogenic variants in more than 100 genes, underlying 2 major groups of Ataxia: autosomal dominant cerebellar Ataxias (ADCA, also known as spinocerebellar Ataxias [SCAs]) due to heterozygous variants or polyglutamine triplet expansions leading to adult-onset Ataxia, and autosomal recessive spinocerebellar Ataxias (ARCAs, also known as SCARs) due to biallelic variants, usually resulting in more severe and earlier-onset cerebellar Ataxia. Certain Ataxia genes, including SPTBN2 which encodes β-III spectrin, are responsible for both SCA and SCAR, depending on whether the pathogenic variant occurs in a monoallelic or biallelic state, respectively. Accordingly, 2 major phenotypes have been linked to SPTBN2: pathogenic heterozygous in-frame deletions and missense variants result in an adult-onset, slowly progressive ADCA (SCA5) through a dominant negative effect, whereas biallelic loss-of-function variants cause SCAR14, an allelic disorder characterized by infantile-onset cerebellar Ataxia and cognitive impairment. Of note, 2 heterozygous missense variants (c.1438C>T, p.R480 W; c.1309C>G, p.R437G), both lying in the second spectrin repeat of SPTBN2, have been linked to infantile-onset cerebellar Ataxia, similar to SCAR14. Here, we report a novel de novo heterozygous pathogenic missense variant (c.1310G>A) in SPTBN2 in a child with infantile-onset cerebellar Ataxia and mild cognitive impairment. This variant affects the same R437 residue of the second spectrin repeat but results in a different amino acid change (p.R437Q). We review previously reported cases and discuss possible pathomechanisms responsible for the early-onset cerebellar phenotype due to disease-causing variants in the second spectrin repeat.
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The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force
The Cerebellum, 2019Co-Authors: Marie Beaudin, José Luiz Pedroso, Hiroshi Mitoma, Mario Manto, Antoni Matilla-dueñas, Bing-weng Soong, Orlando G. Barsottini, Shoji Tsuji, Jeremy D. Schmahmann, Guy A. RouleauAbstract:There is currently no accepted classification of autosomal recessive cerebellar Ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive Ataxias in order to develop a general approach to a patient presenting with Ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international Ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar Ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive Ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with Ataxia. We also identified a list of 48 complex multisystem disorders that are associated with Ataxia and should be included in the differential diagnosis of autosomal recessive Ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.
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mutations in syne1 lead to a newly discovered form of autosomal recessive cerebellar Ataxia
Nature Genetics, 2007Co-Authors: Francois Groslouis, Nicolas Dupre, Patrick A Dion, Michael A Fox, Sandra Laurent, Steve Verreault, Joshua R Sanes, Jeanpierre Bouchard, Guy A. RouleauAbstract:The past decade has seen great advances in unraveling the biological basis of hereditary Ataxias. Molecular studies of spinocerebellar Ataxias (SCA) have extended our understanding of dominant Ataxias. Causative genes have been identified for a few autosomal recessive Ataxias: Friedreich's Ataxia, Ataxia with vitamin E deficiency, Ataxia telangiectasia, recessive spastic Ataxia of Charlevoix-Saguenay and Ataxia with oculomotor apraxia type 1 (refs. 6,7) and type 2 (ref. 8). Nonetheless, genes remain unidentified for most recessive Ataxias. Additionally, pure cerebellar Ataxias, which represent up to 20% of all Ataxias, remain poorly studied with only two causative dominant genes being described: CACNA1A (ref. 9) and SPTBN2 (ref. 10). Here, we report a newly discovered form of recessive Ataxia in a French-Canadian cohort and show that SYNE1 mutations are causative in all of our kindreds, making SYNE1 the first identified gene responsible for a recessively inherited pure cerebellar Ataxia.
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a novel neurodegenerative disease characterised by posterior column Ataxia and pyramidal tract involvement maps to chromosome 8p12 8q12 1
Journal of Medical Genetics, 2004Co-Authors: Paul N Valdmanis, Guy A. Rouleau, A Simoes A Lopes, Francois Groslouis, J D Stewart, Nicolas DupreAbstract:The recent barrage of linkage assignments and gene discoveries has confirmed the clinical and genetic heterogeneity of ataxic diseases. They all share the prototypic feature of difficulty in walking though many additionally present dysarthria, spasticity, retinopathy, and other neurological symptoms.1 Broad subgroups of Ataxias and related diseases exist including spinocerebellar and spastic Ataxias, each with their own characteristic features. The clinical and genetic heterogeneity of Ataxias is best represented by the autosomal dominant cerebellar Ataxias (ADCAs). Indeed, a minimum of 22 loci have been discovered, including those for the spinocerebellar Ataxias (SCA1–8, SCA10–17, SCA19, SCA21, and SCA22),2–8 the episodic Ataxias EA19 and EA2,10 and the complex disorder, dentatorubropallidoluysian atrophy (DRPLA).11 Similarly, Friedreich’s Ataxia (FRDA) is an autosomal recessive disease which affects the spinocerebellar and pyramidal tracts. Symptoms are typically noticed before 20 years of age and include dysarthria, nystagmus, areflexia, and a positive Babinski sign.12 Hereditary spastic Ataxia (HSA) is characterised by retinopathy, muscle wasting, nystagmus, and dysarthria.13 Spastic Ataxia (SAX1) is the first described dominant form,14 while the autosomal recessive spastic Ataxia of Charlevoix-Saguenay (ARSACS) is one of a number of recessive forms.15 All told, the loci responsible for a significant proportion of hereditary causes of Ataxias still have not been elucidated.16 A large amount of heterogeneity is also observed within the hereditary neuropathies. These include the hereditary sensory neuropathies (HSNs)17 and the more common hereditary motor and sensory neuropathies (HMSNs).18 Sensory Ataxia is not present in the HSNs,19 since they affect mainly the unmyelinated and small myelinated nerve fibres, nor is it present in the HMSNs, where sensory symptoms are seldom the presenting complaint. A few rare families have been described with a hereditary sensory-motor neuropathy associated with Ataxia (SMNA) of neuropathic origin.20– …
Henry L Paulson - One of the best experts on this subject based on the ideXlab platform.
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machado joseph disease spinocerebellar Ataxia type 3
Handbook of Clinical Neurology, 2012Co-Authors: Henry L PaulsonAbstract:Abstract Machado–Joseph disease (MJD), also known as spinocerebellar Ataxia type 3 (SCA3), may be the most common dominantly inherited Ataxia in the world. Here I will review historical, clinical, neuropathological, genetic, and pathogenic features of MJD, and finish with a brief discussion of present, and possible future, treatment for this currently incurable disorder. Like many other dominantly inherited Ataxias, MJD/SCA3 shows remarkable clinical heterogeneity, reflecting the underlying genetic defect: an unstable CAG trinucleotide repeat that varies in size among affected persons. This pathogenic repeat in MJD/SCA3 encodes an expanded tract of the amino acid glutamine in the disease protein, which is known as ataxin-3. MJD/SCA3 is one of nine identified polyglutamine neurodegenerative diseases which share features of pathogenesis centered on protein misfolding and accumulation. The specific properties of MJD/SCA3 and its disease protein are discussed in light of what is known about the entire class of polyglutamine diseases.
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caspase mediated proteolysis of the polyglutamine disease protein ataxin 3
Journal of Neurochemistry, 2004Co-Authors: Sarah Shoesmith J Berke, Francisca Flores A Schmied, Ewout Brunt, Lisa M Ellerby, Henry L PaulsonAbstract:Spinocerebellar Ataxia type-3, also known as Machado-Joseph Disease, is one of many inherited neurodegenerative disorders caused by polyglutamine-encoding CAG repeat expansions in otherwise unrelated disease genes. Polyglutamine disorders are characterized by disease protein misfolding and aggregation; often within the nuclei of affected neurons. Although the precise mechanism of polyglutamine-mediated cell death remains elusive, evidence suggests that proteolysis of polyglutamine disease proteins by caspases contributes to pathogenesis. Using cellular models we now show that the endogenous spinocerebellar Ataxia type-3 disease protein, ataxin-3, is proteolyzed in apoptotic paradigms, resulting in the loss of full-length ataxin-3 and the corresponding appearance of an approximately 28-kDa fragment containing the glutamine repeat. Broad-spectrum caspase inhibitors block ataxin-3 proteolysis and studies suggest that caspase-1 is a primary mediator of cleavage. Site-directed mutagenesis experiments eliminating three, six or nine potential caspase cleavage sites in the protein suggest redundancy in the site(s) at which cleavage can occur, as previously described for other disease proteins; but also map a major cleavage event to a cluster of aspartate residues within the ubiquitin-binding domain of ataxin-3 near the polyglutamine tract. Finally, caspase-mediated cleavage of expanded ataxin-3 resulted in increased ataxin-3 aggregation, suggesting a potential role for caspase-mediated proteolysis in spinocerebellar Ataxia type-3 pathogenesis.
Seongman Kang - One of the best experts on this subject based on the ideXlab platform.
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The ubiquitin-conjugating enzyme UbcH6 regulates the transcriptional repression activity of the SCA1 gene product ataxin-1
Biochemical and biophysical research communications, 2008Co-Authors: Soyeon Lee, Sunghoi Hong, Seongman KangAbstract:Spinocerebellar Ataxia type 1 (SCA1) is an autosomal-dominant neurodegenerative disorder characterized by Ataxia and progressive motor deterioration. SCA1 is caused by expansion of the polyglutamine tract in the SCA1 gene product, ataxin-1. We previously reported that the E2 ubiquitin-conjugating enzyme UbcH6 interacts with and ubiquitinates the ataxin-1 proteins as an E2-substrate cognate pair in the ubiquitin-proteasome system. In the present study, we further investigated whether the function of ataxin-1 is associated with UbcH6 and found that UbcH6 regulates the transcriptional repression activity of ataxin-1. The overexpression of UbcH6 reduced the transcriptional repression activity of ataxin-1. Interestingly, ataxin-1(30Q) was more affected by the presence of UbcH6 than ataxin-1(82Q), implying that the length of the polyglutamine tract in ataxin-1 might be involved in determining the stability of ataxin-1. The half-life of ataxin-1(82Q) was longer than that of ataxin-1(30Q) in the presence of UbcH6. shRNAs targeting UbcH6 enhanced the transcriptional repression activity of ataxin-1. In addition, the overexpression of UbcH6 reduced the formation of ataxin-1 aggregates. Our studies demonstrate that UbcH6 modulates the transcriptional repression activity of ataxin-1 by modulating the degradation of ataxin-1, suggesting that UbcH6 may have some therapeutic potential in the treatment of SCA1.
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Proteasome function is inhibited by polyglutamine-expanded ataxin-1, the SCA1 gene product.
Molecules and cells, 2005Co-Authors: Yongjae Park, Sung Jo Kim, Sunghoi Hong, Seongman KangAbstract:Spinocerebellar Ataxia type 1 (SCA1) is an autosomal-dominant neurodegenerative disorder caused by expansion of the polyglutamine tract in the SCA1 gene product, ataxin-1. Using d2EGFP, a short-lived enhanced green fluorescent protein, we investigated whether polyglutamine-expanded ataxin-1 affects the function of the proteasome, a cellular multicatalytic protease that degrades most misfolded proteins and regulatory proteins. In Western blot analysis and immunofluorescence experiments, d2EGFP was less degraded in HEK 293T cells transfected with ataxin-1(82Q) than in cells transfected with lacZ or empty vector controls. To test whether the stability of the d2EGFP protein was due to aggregation of ataxin-1, we constructed a plasmid carrying ataxin-1-Delta114, lacking the self-association region (SAR), and examined degradation of the d2EGFP. Both the level of ataxin-1-Delta114 aggregates and the amount of d2EGFP were drastically reduced in cells containing ataxin-1-Delta114. Furthermore, d2EGFP localization experiments showed that polyglutamine-expanded ataxin-1 inhibited the general function of the proteasome activity. Taken together, these results demonstrate that polyglutamine-expanded ataxin-1 decreases the activity of the proteasome, implying that a disturbance in the ubiquitin-proteasome pathway is directly involved in the development of spinocerebellar Ataxia type1.
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p80 coilin a coiled body specific protein interacts with ataxin 1 the sca1 gene product
Biochimica et Biophysica Acta, 2003Co-Authors: Sunghoi Hong, Sung Jo Kim, Yongjae Park, Seongman KangAbstract:Spinocerebellar Ataxia type 1 (SCA1) is an autosomal-dominant neurodegenerative disorder characterized by Ataxia and progressive motor deterioration. SCA1 is associated with an elongated polyglutamine tract in ataxin-1, the SCA1 gene product. Using the yeast two-hybrid system and co-immunoprecipitation experiments, we have found that p80 coilin, coiled body-specific protein, binds to ataxin-1. In further experiments with deletion mutants, we found that the C-terminal regions of ataxin-1 and p80 coilin were essential for this interaction. In HeLa cells that have been co-transfected with ataxin-1 and p80 coilin, the p80 coilin protein co-localizes with ataxin-1 aggregates in the nucleoplasm. However, immunohistochemical analysis and immunofluorescence assays showed that mutant ataxin-1 aggregates do not redistribute p80 coilin's dot-like structures in the Purkinje cells of SCA1 transgenic mice. This feature of the interaction between ataxin-1 and p80 coilin suggests that p80 coilin might be implicated in altering the function of ataxin-1.
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USP7, a ubiquitin-specific protease, interacts with ataxin-1, the SCA1 gene product.
Molecular and cellular neurosciences, 2002Co-Authors: Sunghoi Hong, Sung Jo Kim, Inho Choi, Seongman KangAbstract:Abstract Spinocerebellar Ataxia type 1 (SCA1) is an autosomal-dominant neurodegenerative disorder characterized by Ataxia and progressive motor deterioration. SCA1 has been known to associate with elongated polyglutamine tract in ataxin-1, the SCA1 gene product. Using the yeast two-hybrid system, we have found that USP7, a ubiquitin-specific protease, binds to ataxin-1. Further experiments with deletion mutants indicated that the C-terminal region of ataxin-1 was essential for the interaction. Liquid β-galactosidase assay and coimmunoprecipitation experiments revealed that the strength of the interaction between USP7 and ataxin-1 is influenced by the length of the polyglutamine tract in the ataxin-1; weaker interaction was observed in mutant ataxin-1 with longer polyglutamine tract and USP7 was not recruited to the mutant ataxin-1 aggregates in the Purkinje cells of SCA1 transgenic mice. Our results suggest that altered function of the ubiquitin system can be involved in the pathogenesis of spinocerebellar Ataxia type 1.
Pamela J. Skinner - One of the best experts on this subject based on the ideXlab platform.
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Amino acids in a region of ataxin-1 outside of the polyglutamine tract influence the course of disease in SCA1 transgenic mice
NeuroMolecular Medicine, 2002Co-Authors: Pamela J. Skinner, Cynthia A. Vierra-green, Effat Emamian, Huda Y. ZoghbiAbstract:Spinocerebellar Ataxia type 1 (SCA1) belongs to a family of polyglutamine induced neurodegenerative disorders. Transgenic mice that overexpress a mutant allele of the SCA1 gene develop a progressive Ataxia and Purkinje cell pathology. In this report, the pathological importance of a segment of ataxin-1 previously shown to be important for protein-protein interactions was examined. While the absence of a 122 amino acid segment from the protein-protein interaction region of ataxin-1 did not effect the initiation of disease, its absence substantially suppressed the progression of disease in SCA1 transgenic mice. Thus, these data suggest that this region of ataxin-1 has a role in disease progression. Furthermore, these results provide evidence that ataxin-1-induced disease initiation and disease progression involve distinct molecular events.
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ataxin 1 nuclear localization and aggregation role in polyglutamine induced disease in sca1 transgenic mice
Cell, 1998Co-Authors: Ivan A Klement, Michael D Kaytor, Pamela J. Skinner, Hong Yi, Steven M Hersch, Brent H Clark, Huda Y. ZoghbiAbstract:Abstract Transgenic mice carrying the spinocerebellar Ataxia type 1 (SCA1) gene, a polyglutamine neurodegenerative disorder, develop Ataxia with ataxin-1 localized to aggregates within cerebellar Purkinje cells nuclei. To examine the importance of nuclear localization and aggregation in pathogenesis, mice expressing ataxin-1[82] with a mutated NLS were established. These mice did not develop disease, demonstrating that nuclear localization is critical for pathogenesis. In a second series of transgenic mice, ataxin-1[77] containing a deletion within the self-association region was expressed within Purkinje cells nuclei. These mice developed Ataxia and Purkinje cell pathology similar to the original SCA1 mice. However, no evidence of nuclear ataxin-1 aggregates was found. Thus, although nuclear localization of ataxin-1 is necessary, nuclear aggregation of ataxin-1 is not required to initiate pathogenesis in transgenic mice.
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ataxin 1 with an expanded glutamine tract alters nuclear matrix associated structures
Nature, 1997Co-Authors: Pamela J. Skinner, Huda Y. Zoghbi, Ivan A Klement, Beena T Koshy, Christopher J Cummings, Kara Helin, Antonio Servadio, Harry T OrrAbstract:Spinocerebellar Ataxia type 1 (SCA1) is one of several neurodegenerative disorders caused by an expansion of a polyglutamine tract1,2. It is characterized by Ataxia, progressive motor deterioration, and loss of cerebellar Purkinje cells1. To understand the pathogenesis of SCA1, we examined the subcellular localization of wild-type human ataxin-1 (the protein encoded by the SCA1 gene) and mutant ataxin-1 in the Purkinje cells of transgenic mice3. We found that ataxin-1 localizes to the nuclei of cerebellar Purkinje cells. Normal ataxin-1 localizes to several nuclear structures ∼0.5 µm across, whereas the expanded ataxin-1 localizes to a single ∼2-µm structure, before the onset of Ataxia. Mutant ataxin-1 localizes to a single nuclear structure in affected neurons of SCA1 patients. Similarly, COS-1 cells transfected with wild-type or mutant ataxin-1 show a similar pattern of nuclear localization; with expanded ataxin-1 occurring in larger structures that are fewer in number than those of normal ataxin-1. Colocalization studies show that mutant ataxin-1 causes a specific redistribution of the nuclear matrix-associated domain containing promyelocytic leukaemia protein4,5,6,7. Nuclear matrix preparations demonstrate that ataxin-1 associates with the nuclear matrix in Purkinje and COS cells. We therefore propose that a critical aspect of SCA1 pathogenesis involves the disruption of a nuclear matrix-associated domain.
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ataxin 1 with an expanded glutamine tract alters nuclear matrix associated structures
Nature, 1997Co-Authors: Pamela J. Skinner, Huda Y. Zoghbi, Ivan A Klement, Beena T Koshy, Christopher J Cummings, Kara Helin, Antonio Servadio, Harry T OrrAbstract:Spinocerebellar Ataxia type 1 (SCA1) is one of several neurodegenerative disorders caused by an expansion of a polyglutamine tract. It is characterized by Ataxia, progressive motor deterioration, and loss of cerebellar Purkinje cells. To understand the pathogenesis of SCA1, we examined the subcellular localization of wild-type human ataxin-1 (the protein encoded by the SCA1 gene) and mutant ataxin-1 in the Purkinje cells of transgenic mice. We found that ataxin-1 localizes to the nuclei of cerebellar Purkinje cells. Normal ataxin-1 localizes to several nuclear structures approximately 0.5 microm across, whereas the expanded ataxin-1 localizes to a single approximately 2-microm structure, before the onset of Ataxia. Mutant ataxin-1 localizes to a single nuclear structure in affected neurons of SCA1 patients. Similarly, COS-1 cells transfected with wild-type or mutant ataxin-1 show a similar pattern of nuclear localization; with expanded ataxin-1 occurring in larger structures that are fewer in number than those of normal ataxin-1. Colocalization studies show that mutant ataxin-1 causes a specific redistribution of the nuclear matrix-associated domain containing promyelocytic leukaemia protein. Nuclear matrix preparations demonstrate that ataxin-1 associates with the nuclear matrix in Purkinje and COS cells. We therefore propose that a critical aspect of SCA1 pathogenesis involves the disruption of a nuclear matrix-associated domain.
