Human Molecular Genetics, 2001, Vol. 10, No. 20 2307-2311
© 2001 Oxford University Press
SCA1 molecular genetics: a history of a 13 year collaboration against glutamines
Institute of Human Genetics, Department of Laboratory Medicine and Pathology, Department of Genetics, Cell Biology and Development, University of Minnesota, Mayo Mail Code 206, Minneapolis, MN 55455, USA and 1Howard Hughes Medical Institute, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Received July 26, 2001; Accepted July 31, 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONTHE POSITIONAL CLONING PERIODTHE FIRST ANIMAL MODEL...THE MOLECULAR/CELLULAR PERIODSCA1 RESEARCH: THE NEXT...REFERENCES |
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Spinocerebellar ataxia type 1 (SCA1) is a relatively rare autosomal-dominant neurological disorder. SCA1 has the intriguing feature that the disease-causing mutation is the expansion of an unstable trinucleotide repeat, specifically a CAG repeat that encodes the amino acid glutamine in ataxin-1. During the past 10 years, substantial progress has been made towards understanding the pathogenic mechanism in this disease. The nucleus has been identified as the subcellular site where the mutant protein acts to cause disease. Evidence indicates that expansion of the glutamine tract alters the folding properties of ataxin-1. Finally, several cellular pathways have been identified which are able to impinge on the SCA1 disease process. The characterization of these pathways and their role in SCA1 will guide research over the next several years.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONTHE POSITIONAL CLONING PERIODTHE FIRST ANIMAL MODEL...THE MOLECULAR/CELLULAR PERIODSCA1 RESEARCH: THE NEXT...REFERENCES |
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In commemoration of the tenth anniversary of Human Molecular Genetics, we review the important contributions that molecular genetic approaches have made towards understanding the neurological disease spinocerebellar ataxia type 1 (SCA1). SCA1 is an autosomal-dominant neurodegenerative disease typically with mid-life onset characterized by motor symptoms in the absence of cognitive deficits. Death usually occurs between 10 and 15 years after the onset of symptoms. The clinical features of SCA1 vary depending on the stage of the disease, but typically in addition to ataxia, include dysarthria, and swallowing and breathing problems. At the pathological level, the most frequent and severe alterations seen in SCA1 patients are the loss of Purkinje cells in the cerebellar cortex, and degeneration of neurons in the inferior olivary nuclei, the cerebellar dentate nuclei and the red nuclei. Nuclei of the third, tenth and twelfth cranial nerves also have variable involvement, with the hypoglossal nuclei being the most frequently and severely affected (1).
Genetic contributions to SCA1 research are particularly notable since they extend from the identification of its mutational basis to the elucidation of pathways that alter disease progression. While the efforts of several research groups have contributed to molecular genetic research on SCA1, we have chosen to frame our comments in the context of the 13 year collaboration between our laboratories. Like the contributions of molecular genetics to SCA1 research, our collaboration on SCA1 extends back to its cloning and continues as pathogenesis is being elucidated at the cellular and molecular levels.
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THE POSITIONAL CLONING PERIOD |
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TOPABSTRACTINTRODUCTIONTHE POSITIONAL CLONING PERIODTHE FIRST ANIMAL MODEL...THE MOLECULAR/CELLULAR PERIODSCA1 RESEARCH: THE NEXT...REFERENCES |
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Application of genetics to SCA1 research began in the last half of the nineteenth century. Between 1863 and 1877, Friedreich described a recessive form of hereditary ataxia that today bears his name (2,3). In 1893, Pierre Marie (4) noticed a form of ataxia in four families with a clinical picture distinct from that described by Friedreich. Despite extensive criticism to classifying this entity distinct from that described by Freidreich, because of its heterogeneous clinical presentation, ataxias recognized by Marie have evolved into the large class of disorders classified today as the autosomal dominant ataxias or spinocerebellar ataxias (SCAs). It is important to note, however, that the autosomal dominant ataxias remained difficult to classify based on clinical or pathological findings. A major step towards a definitive classification came with the linkage of one form of ataxia, SCA1, with the HLA complex and chromosome 6p (5).
The first use of DNA markers to map an ataxia gene was in the localization of SCA1 to a region 15 cM distal to the HLA complex (6). Subsequently, DNA marker D6S89 impacted SCA1 research in two important ways. First, this marker proved to be very effective in the genetic classification of an ataxia as SCA1 (7,8). In addition, D6S89 was the ‘molecular’ basis behind the collaborative linkup between our two laboratories. While our groups were in contact and exchanged reagents and data, we had not discussed a formal collaboration. Until our respective labs got the results using D6S89 as a marker, it was unclear whether our groups were seeking to clone the same ataxia locus. Once the D6S89 linkage data were obtained, it was clear that the two large ataxia families being used at the University of Minnesota and at Baylor College of Medicine were affected by a mutation at the same SCA locus, in 6p23. It was a phone call from Dr Huda Y.Zoghbi that got the collaboration rolling. Huda’s proposal to work together made scientific sense and was put in such a way that it was clear it would be fun.
By the spring of 1993, the SCA1 critical region was mapped to a <2 cM segment on 6p (9). In addition, anticipation was a clear clinical feature of the disease in the large Minnesota and Baylor SCA1 families (10,11). Taking a cue from the evidence that anticipation is due to the expansion of a trinucleotide repeat (12–18), we devised a directed strategy to determine whether repeat expansion caused SCA1. The definitive experiment was a Southern blot utilizing DNA from a juvenile case of SCA1. Subsequent molecular characterization of the SCA1 gene and its transcript revealed that the CAG repeat is in the coding region encoding a polyglutamine tract (19–23). Disease severity and age of onset were shown to be directly associated with the length of the mutant CAG repeat. Mutant unstable SCA1 alleles contain pure repeat tracts consisting of 41 or more CAGs. On the other hand, the repeat tract of stable wild-type alleles ranges from six to 44 triplets with alleles longer than 20 having at least one and up to three CAT interruptions. The deposition of CAT interruptions within wild-type alleles having more than 20 repeats suggests that these interruptions may have a role in stabilizing these alleles, rendering them unsusceptible to intergenerational instabilities. Similarly, interruptions in wild-type alleles of Fragile X contribute to their stability (24).
Characterization of SCA1 revealed that it encoded a novel protein of about 800 amino acids; the absolute length depends on the number of CAG and CAT triplets. The SCA1 gene spans 450 kb and consists of nine exons. The SCA1 transcript was unique in that the 5'-untranslated region (5'-UTR) was encoded by exons 1–7 and a portion of exon 8. In addition, the 3'-UTR encoded by the last exon extended for 7277 bases, at that time the longest 3'-UTR in GenBank. Expression analysis revealed that mRNA was expressed equally from both the wild-type and mutant alleles.
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THE FIRST ANIMAL MODEL OF A POLYGLUTAMINE DISEASE |
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With the cloning of SCA1, we quickly proceeded to the generation of mice expressing SCA1 cDNA transgenes. This was also the first time in our collaboration that we had to decide that each laboratory would focus on a specific area of research. So while the Zoghbi laboratory constructed a full-length SCA1 cDNA, the Orr lab focused on the initial characterization of the CAG repeat in mutant and wild-type alleles. Then, while the Orr lab generated the first SCA1 transgenics and evaluated Sca1 expression during mouse embryogenesis, the Zoghbi lab began to generate Sca1 knock-out mice and developed antibodies to the SCA1-encoded protein, ataxin-1. This division of labor, so to speak, has been the mode of operation of our collaboration ever since the SCA1 gene was cloned.
The strategy used in the establishment of the first SCA1 transgenic mice was predicated on several points (25). First, we focused on developing a model that would allow us to examine pathogenesis in a single cell type that is a prominent site of neuropathology in SCA1, the Purkinje cells of the cerebellar cortex. To obtain a mouse that had the best chance of having a robust phenotype of relevance to the human disease, we used a full-length mutant SCA1 cDNA allele with a large repeat expansion, 82 CAGs, that in humans results in a juvenile form of SCA1. The strong, Purkinje cell-specific regulatory region from the murine Pcp-2 gene directed its expression. As controls, mice expressing high levels of a wild-type SCA1 cDNA with 30 glutamines (30Q) were also established and characterized.
In transgenic mice from an ataxin-1(30Q) line, ataxin-1 localized to several 
0.5 µm nuclear inclusions. In contrast, in ataxin-1(82Q) mice ataxin-1 localized to a single 2 µm ubiquitinated nuclear aggregate, similar to what was seen in tissue from patients with SCA1 (26). The appearance of these aggregates, which stained immunohistochemically for the 20S proteasome and the HDJ-2/HSDJ (Hsp40) chaperone protein (27), preceded the onset of ataxia by 6 weeks. SCA1 transgenic animals from the ataxin-1(82Q) line had mild cerebellar impairment at 5 weeks of age; there was no evidence of gait abnormalities or balance problems at that age (28). By 12 weeks, the motor skill impairment progressed to overt ataxia, which worsened over time.
The first histological change detected was the development of cytoplasmic, membranous vacuoles within Purkinje cell bodies at postnatal day 25 (28). At 6 weeks of age, a loss of proximal dendritic branches and a decrease in the number of dendritic spines became apparent. By 12–15 weeks, the complexity of the dendritic arborization of Purkinje cells was markedly reduced and the molecular layer was atrophic. Thus, transgenic mouse Purkinje cells that overexpress a mutant allele of the SCA1 gene developed two morphological features seen in brain material from SCA1 patients: atrophy of the Purkinje cell dendritic tree and the presence of nuclear aggregates of ataxin-1. These observations indicate that the SCA1 mice are undergoing a disease process that is very similar to that seen in the humans. Importantly, Purkinje cell loss was minimal at the time of progressive gait abnormality. Thus, the SCA1 transgenic mice indicated that the neurological impairment is due to neuronal dysfunction and not directly the result of neuronal loss.
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Once we had developed and characterized a transgenic model of SCA1-induced disease in mice, we moved on to the identification of cellular pathways that had the capability of impacting on disease. To ascertain whether ataxin-1 must be in the nucleus to cause disease, mice that express expanded ataxin-1(82Q) with a mutated nuclear localization sequence, ataxin-1K772T, were generated and characterized (29). Although these mice expressed high levels of ataxin-1 in Purkinje cells, similar to those observed in the original SCA1, ataxin-1(82Q) transgenic mice, they never developed Purkinje cell pathology or motor dysfunction. Ataxin-1 was diffusely distributed throughout the cytoplasm and formed no aggregates, even when the mice were 1 year old. Nuclear localization is clearly critical for pathogenesis and ataxin-1 aggregation. Furthermore, the ataxin-1K772T mice expressed levels of SCA1 mRNA as high as the ataxin-1(82Q) mice did, yet they failed to develop disease. Thus, these studies provided direct evidence that it is the ataxin-1 protein with an expanded number of glutamine residues that is pathogenic and not SCA1 RNA with an expanded number of CAG triplet repeats.
To assess the role of nuclear aggregates in causing disease, we generated transgenic mice using ataxin-1(77Q) with amino acids deleted from the self-association region found to be essential for ataxin-1 dimerization (29). These mice developed ataxia and Purkinje cell pathology similar to the original ataxin-1(82Q) transgenic mice, but without detectable nuclear ataxin-1 aggregates at either the light or electron microscopic levels. Thus, although nuclear localization of ataxin-1 is necessary, nuclear aggregation of ataxin-1 appears not to be required for initiation of Purkinje cell pathogenesis in transgenic mice. It is important to note that the deletion of 122 amino acids might have compromised ataxin-1 in various ways, e.g. its folding, turnover rate, or ability to interact with other cellular factors. This seems unlikely since this truncated ataxin-1 retained its ability to produce all of the neurobehavioral and unique pathologic features observed in the ataxin-1(82Q) mice.
Immunohistochemical studies of material from SCA1 patients and transgenic mice, as well as cell culture studies, strongly indicated that the ubiquitin proteasomal pathway (UPP) was implicated in the processing of mutant ataxin-1 (27). As a test of the role of the UPP in SCA1, we crossed ataxin-1(82Q) transgenic mice with mice lacking expression of the Ube3a gene (30). Ube3a encodes the E6-associated protein, E6-AP, which is an E3 ubiquitin ligase. Two important observations were made in the double mutant mice, i.e. mice expressing the full-length ataxin-1(82Q) protein in the absence of Ube3a expression. The presence of nuclear aggregates of ataxin-1(82Q) was reduced significantly both in terms of their frequency and their size. Yet, the Purkinje cell pathology was markedly worse compared to that seen in the ataxin-1(82Q) mice. These studies demonstrated that perturbations in a key enzyme in the ubiquitination pathway interfered with the formation of the nuclear inclusions. Furthermore, they showed that pathology is not dependent on the formation of nuclear inclusions. In fact, it seems that when ataxin-1 is not sequestered in these inclusions its pathogenic effects in Purkinje cells are more pronounced (27). The SCA1 transgenic mice studies provide two distinct examples in which nuclear inclusions are shown not to be necessary for the development of polyglutamine-induced neuronal disease.
Another cellular process with the potential to alter polyglutamine-induced disease involves components of the cellular protein-folding machinery. Overexpressing specific chaperones in transfected cells reduces mutant ataxin-1 aggregation (27). In this case, reduction of inclusions would be predicted to be beneficial as it is the result of either refolding of ataxin-1 or enhanced clearance via the proteasome. This is what happens in vivo where chaperones suppress neurodegeneration in fly models of ataxin-1 and other polyglutamine disease proteins (31–34). To assess whether enhanced chaperone function could alter disease in the mouse model of SCA1, we bred the SCA1 mice with mice overexpressing a molecular chaperone, inducible heat-shock protein 70 (iHSP70) (35). Increased iHSP70 mitigated mutant ataxin-1-induced loss of motor function as well as Purkinje cell pathology. Interestingly, iHSP70 expression did not alter the formation of ataxin-1 nuclear inclusions.
What are the consequences of having misfolded ataxin-1 in Purkinje cells? Some insight into the molecular basis of mutant ataxin-1 pathogenicity was recently obtained by the observation that an expanded allele of SCA1 has the ability to alter Purkinje cell gene expression early on in the SCA1 transgenic mice (36). Using the SCA1 transgenic mice and a PCR-based cDNA subtractive hybridization strategy, several genes, all expressed by Purkinje cells, were found to be downregulated at an early stage of disease, prior to any detectable pathological or neurological alteration. Interestingly, a number of the genes found to be downregulated encoded proteins involved in neuronal calcium signaling. These included inositol triphosphate receptor type 1, sarcoplasmic endoplasmic reticulum calcium ATPase type 2, transient receptor potential type 3 and inositol polyphosphate 5-phosphatase type 1 (36). Intriguingly, all of the genes whose expression was altered early on in the SCA1 transgenic mice were downregulated. The mechanism of this downregulation could involve either transcription and/or post-transcription events. Since ataxin-1 has RNA-binding activity in vitro and may bind RNA in vivo (37), it is possible to speculate that the downregulation in gene expression seen in SCA1 involves a mechanism at the RNA level.
Another strategy we have utilized to assess possible functions for ataxin-1 has been to identify protein interactors using the yeast two-hybrid system. Using this strategy, we showed that ataxin-1 has the ability to self-associate, regardless of glutamine repeat length, and the domain mediating this interaction was delineated using the yeast two-hybrid system (38). In addition, the nuclear protein LANP was identified as an ataxin-1 interactor utilizing the yeast two-hybrid system (39). LANP is predominantly expressed in nuclei of cerebellar Purkinje cells. Quantitative ß-galactosidase assays on co-transformed yeast colonies demonstrated that ataxin-1 harboring an expanded polyglutamine tract has a stronger interaction with LANP than does wild-type ataxin-1. More recently, we isolated the complete cDNA of a novel ataxin-1 interacting ubiquitin-like protein, designated A1Up (40). Sequence comparisons revealed that A1Up contains an N-terminal ubiquitin-like region. A1Up also has substantial homology to human Chap1/Dsk2, a protein that binds the ATPase domain of the HSP70-like Stch protein. Perhaps A1Up may link ataxin-1 processing to the chaperone and ubiquitin/proteasome pathways.
Given the power of Drosophila genetics for elucidating molecular pathways, the next logical animal model to develop was an SCA1 fly model. Using the GAL4-UAS system, flies that express either wild-type full-length ataxin-1 (ataxin-1-30Q) or mutant ataxin-1 (82Q) were generated in the laboratory of Juan Botas at Baylor (32). Mutant ataxin-1 induced progressive degeneration in the fly neurons and recapitulated many of the cellular changes seen in mammalian cells. To our surprise, wild-type ataxin-1, when expressed at sufficiently high levels, induced many of the pathologic changes caused by the mutant protein, albeit not to the same degree of severity. This prompted us to evaluate the effects of over-expression of wild-type ataxin-1 in mice, and indeed we found mild Purkinje cell degeneration in aged mice overexpressing the wild-type protein. These data provided the first clue that the expanded polyglutamine tract in ataxin-1 could be increasing ataxin-1 levels (because of inefficient clearance) or increasing the protein’s likelihood of taking on a misfolded conformation that occasionally occurs with the wild-type protein. The SCA1 flies were subsequently used to identify genes that either suppress or enhance the neurodegenerative phenotype when their expression levels are altered. Several genes involved in the UPP and protein folding pathways were identified, which is consistent with the studies in cell culture and transgenic mice. Interestingly, other modifiers supported the importance of RNA processing, transcription regulation, cellular detoxification and nuclear transport in disease. Given the important role of nuclear localization of ataxin-1 for pathogenicity in mice, its potential role as an RNA binding protein, and the effects of mutant ataxin-1 on gene expression in Purkinje cells, these novel modifiers provide an avenue for pursuing the in vivo role of ataxin-1 in these pathways. The finding that HSP70 overexpression subdues ataxin-1 toxicity in flies and mice (35) provides the first evidence that a cross-species approach to study the modifiers is likely to prove fruitful.
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SCA1 RESEARCH: THE NEXT PERIOD |
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TOPABSTRACTINTRODUCTIONTHE POSITIONAL CLONING PERIODTHE FIRST ANIMAL MODEL...THE MOLECULAR/CELLULAR PERIODSCA1 RESEARCH: THE NEXT...REFERENCES |
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Two major features of the molecular basis of SCA1 guide our research at this time (Fig. 1). The realization that mutant ataxin-1 causes disease upon entering the nucleus has prompted efforts to understand the regulation of its nuclear localization and its function in the nucleus. Secondly, understanding that expansion of the polyglutamine tract alters the folding of ataxin-1 highlighted the importance of protein folding and clearance in pathogenesis. The seminal nature these two pathways play in SCA1 was heightened upon the demonstration that they are strong modifiers of ataxin-1-induced neurodegeneration in Drosophila (32).
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Eukaryotic cells have developed several means by which to regulate the movement of proteins between the cytoplasm and the nucleus. The hypothesis that ataxin-1 transport to the nucleus might be regulated is indicated by the observation that its level in the nucleus varies between cell types. At one extreme are transfected COS cells where the nuclear levels of ataxin-1 are very prominent. In contrast, in B-lymphoblastoid cells the nucleus appears to essentially devoid of ataxin-1. Known transport across the nuclear envelope occurs through the nuclear pore complex (NPC). Signal-mediated transport, among other things, requires a nuclear localization signal (NLS) which interacts with soluble components of the transport machinery, the importins. The importin–cargo complex is targeted to the NPC. In Purkinje cells, an important site of SCA1 pathology, the functional ataxin-1 NLS is a classic monopartate basic NLS located at the C-terminus. A primary means by which nuclear transport is regulated involves regulating the affinity of the cargo protein for its importin receptor. This regulation is often accomplished by either phosphorylation of the cargo or by association of the cargo with accessory proteins. Both of these strategies are being examined to determine whether either or both have a role in regulating transport of ataxin-1 to the nucleus.
Having established that protein levels are significant in modulating pathogenesis and that protein clearance is at the root of the disease, significant effort will be directed toward identifying the precise factors involved in the degradation of ataxin-1. What kind of modifications might ataxin-1 undergo? What is ataxin-1’s E3 ligase? Is ataxin-1’s degradation occurring in the nucleus or cytoplasm? Such questions will be answered using a combination of genetic, biochemical and cell biological approaches. The fly models will provide in vivo candidate genes that can be further investigated in cells and mice. In addition, we will pursue the study of key suppressors identified in Drosophila, as these might provide targets for therapeutic intervention in the future.
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ACKNOWLEDGEMENTS |
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We sincerely thank all of the members of our laboratories, past and present, whose efforts have contributed to the SCA1 collaboration. NIH/NINDS grants NS22920 (H.T.O.) and NS27699 (H.Y.Z.) supported this work. H.Y.Z. is a Howard Hughes Medical Institute Investigator.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +1 612 625 3647; Fax: +1 612 626 2600; Email: harry@lenti.med.umn.edu
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TOPABSTRACTINTRODUCTIONTHE POSITIONAL CLONING PERIODTHE FIRST ANIMAL MODEL...THE MOLECULAR/CELLULAR PERIODSCA1 RESEARCH: THE NEXT...REFERENCES |
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