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At least 19 recordsLinked to original sources

PubMed2003

Elucidation of ataxin-3 and ataxin-7 function by integrative bioinformatics.

The spinocerebellar ataxias (SCAs) are a class of hereditary neurodegenerative diseases, which are caused by the pathological expansion of unstable CAG triplet repeats found in a number of apparently unrelated genes. The proteins encoded by the SCA genes typically translate this expanded (CAG)n repeat into an expanded poly(Q) stretch. Several pathological features are common to all SCAs, irrespective of the gene harbouring the expansion. The specific contributions of the mutated genes are currently hard to assess, as the physiological role of most of the so-called ataxins is not known. By combining the results of profile-based sequence analysis with genome-wide functional data available for model organisms, we have derived detailed predictions of the physiological function of two SCA gene products. Ataxin-3, the protein mutated in Machado Joseph Disease (SCA3), belongs to a novel group of cysteine-proteases and is predicted to be active against ubiquitin chains or related substrates. The catalytic site of this enzyme class is similar to that found in UBP and UCH type ubiquitin proteases. For ataxin-7, the gene product of the SCA7 gene, we have identified an orthology relationship to the yeast open reading frame Ygl066c. Recently published evidence from genome-wide studies suggests that Ygl066c is a component of the SAGA histone acetyltransferase complex. By analogy, a similar role for the mammalian ataxin-7 can be expected. The functional predictions reported here are sufficiently precise to allow a direct experimental verification. Moreover, both findings have implications for the general pathogenesis of spinocerebellar ataxias by providing a direct connection of these diseases with ubiquitin metabolism and histone acetylation.

Acetylation↗

PubMed1999

Ataxin 1 and ataxin 3 in neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a multisystem neurodegenerative disorder characterized by large intranuclear aggregates in neurons of the central and peripheral nervous system. These ubiquitinated intranuclear inclusions are morphologically similar to the intraneuronal aggregates that have been identified in the CAG/polyglutamine expansion diseases. As rare aggregates in NIID contain a polyglutamine epitope, we further investigated the relationship between this disease and the CAG/polyglutamine expansion diseases. Here, we show that ataxin 1 and ataxin 3 proteins are recruited into aggregates in NIID in the absence of a CAG expansion in the SCA1 and SCA3 genes. These data support an association of NIID with the polyglutamine disorders and provide evidence of in vivo recruitment of proteins with polyglutamine tracts into intraneuronal aggregates.

Adult↗

PubMedDate not supplied

Localization of ataxin-2 within the cerebellar cortex of the rat.

Spinocerebellar ataxia type 2 is caused by a polyglutamine stretch in the protein ataxin-2 that is due to an expansion of a CAG repeat in the spinocerebellar ataxia-2 gene. The function of wild-type ataxin-2 has not been clarified. A widespread distribution of this protein throughout the brain has been reported. We examined the expression of ataxin-2 in cortical cerebellar cells of the adult rat. We performed a single label immunohistochemical study of ataxin-2 and a single label immunofluorescence study of ataxin-2 and zebrin on adjacent sections, to compare the distribution of the observed parasagittal band pattern. We also performed a double label immunofluorescence study of ataxin-2 and one of each parvalbumin, calbindin, and calretinin. Single label studies revealed that between 50% and 70% of the Purkinje cells express ataxin-2. The abundance of ataxin-2 was different between hemisphere and vermis, with a clear prevalence for the former. Furthermore, the distribution of ataxin-2-positive Purkinje cells showed a peculiar alternating parasagittal band pattern. Among the other cortical cerebellar cells only basket and granule cells showed ataxin-2 staining. Our dual label studies showed that about 50% of calbindin and more than 70% of parvalbumin-immunoreactive Purkinje cells were also labeled for ataxin-2. The uneven distribution of ataxin-2 expression in the Purkinje cell layer does not support the hypothesized link between ataxin-2 content and cell vulnerability. The differences in ataxin-2 expression among the cell types of cerebellar cortex, on the other hand, suggest a possible correlation between ataxin-2 content and cell function.

Animals↗

PubMed2000

Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder caused by an expansion of the polyglutamine tract near the C-terminus of the MJD1 gene product, ataxin-3. The mutant ataxin-3 forms intranuclear inclusions in cultured cells as well as in diseased human brain and also causes cell death in transfected cells. However, the normal function of ataxin-3 remains unknown. To explore the function of ataxin-3, we used the two-hybrid system to screen for the protein(s) that interacts with ataxin-3. We found that ataxin-3 interacts with two human homologs of the yeast DNA repair protein RAD23, HHR23A and HHR23B. Furthermore, we confirmed that ataxin-3 interacts with the -ubiquitin-like domain at the N-terminus of the HHR23 proteins, which is important for nucleotide excision repair; however, ataxin-3 does not interact with -ubiquitin, implying that ataxin-3 might be functionally associated with the HHR23 proteins through this specific interaction. The normal and mutant ataxin-3 proteins show no difference in their ability to bind to the HHR23 proteins. However, in 293 cells HHR23A is recruited to intranuclear inclusions formed by the mutant ataxin-3 through its interaction with ataxin-3. These results suggest that this interaction is associated with the normal function of ataxin-3 and that some functional abnormality of the HHR23 proteins might exist in MJD.

Ataxin-3↗

PubMed2000

Expression analysis of ataxin-7 mRNA and protein in human brain: evidence for a widespread distribution and focal protein accumulation.

Spinocerebellar ataxia 7 (SCA7) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG-trinucleotide repeat in the coding region of the SCA7 gene. The expansion is translated into an extended polyglutamine stretch in the protein ataxin-7, a protein of unknown function. By Northern blot analysis expression of ataxin-7 was detected in numerous regions of human brain and some peripheral tissues. It is unknown, however, if ataxin-7 is enriched at sites of the SCA7 pathology. We studied the regional and cellular expression pattern of ataxin-7 at the mRNA level by in situ hybridization histochemistry in normal human brain. Furthermore we used a monoclonal and two polyclonal antibodies raised against the normal ataxin-7 to establish the distribution of this protein in brain, retina and peripheral organs. At the mRNA level ataxin-7 was preferentially expressed in neurons; the regional distribution reflected neuronal packing density. Ataxin-7 immunoreactivity (IR) was similarly widely expressed. In most neurons, ataxin-7 IR was preferentially localized to the cytoplasmatic compartment although some nuclear ataxin-7 IR was detected in most neurons. A more intense and more prominently nuclear ataxin-7 IR was observed in neurons of the pons and the inferior olive, brain regions severly affected by the disease, suggesting that the subcellular localization and abundance of ataxin-7 is regulated in a regionally specific way. Since neurons displaying more intense and more prominently nuclear ataxin-7 IR belonged to the class of susceptible cells in SCA7, an enrichment of normal ataxin-7 in the nuclear compartment may contribute to neurodegeneration. However not all sites of SCA7 pathology displayed a strong cytoplasmatic and nuclear immunoreactivity.

Ataxin-7↗

PubMed1997

Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures.

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.

Animals↗

PubMed2000

Ataxin-3 is translocated into the nucleus for the formation of intranuclear inclusions in normal and Machado-Joseph disease brains.

Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) is one of the dominantly inherited cerebellar ataxias. The gene responsible for the disease, a novel gene of unknown function, encodes ataxin-3 containing a polyglutamine stretch. Although it has been known that ataxin-3 is incorporated into neuronal intranuclear inclusions (NIIs) in neurons of affected regions, the relationship between NII formation and neuronal degeneration still remains uncertain. In the present study we show two different conditions in which ataxin-3 is recruited into the nucleus and suggest a process to form nuclear inclusions. In normal brains, wild-type ataxin-3 localizes within the ubiquitin-positive nuclear inclusion, the Marinesco body, indicating that ataxin-3 is recruited into the nuclear inclusion even in the absence of pathologically expanded polyglutamine. In MJD/SCA3 brains, immunohistochemical analyses with anti-ataxin-3 antibody, anti-ubiquitin antibody, and monoclonal antibody 1C2 known to recognize expanded polyglutamine revealed differences in frequency and in diameter among NIIs recognized by each antibody. These results were confirmed in the same inclusions by double immunofluorescent staining, suggesting that expanded ataxin-3 forms a core, thereby recruiting wild-type ataxin-3 into the nucleus around the core portion, and then followed by activation of the ubiquitin/ATP-dependent pathway. Recruitment of ataxin-3 into the nucleus and formation of nuclear inclusion under two different conditions suggest that ataxin-3 may be translocated into the nucleus under certain conditions stressful on neuronal cells such as aging and polyglutamine neurotoxicity.

Ataxin-3↗

PubMed1998

An isoform of ataxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients.

Autosomal dominant spinocerebellar ataxias (SCA) form a group of clinically and genetically heterogeneous neurodegenerative disorders. The defect responsible for SCA3/Machado-Joseph disease (MJD) has been identified as an unstable and expanded (CAG)n trinucleotide repeat in the coding region of a novel gene of unknown function. The MJD1 gene product, ataxin-3, exists in several isoforms. We generated polyclonal antisera against an alternate carboxy terminus of ataxin-3. This isoform, ataxin-3c, is expressed as a protein of approximately 42 kDa in normal individuals but is significantly enlarged in affected patients confirming that the CAG repeat is part of the ataxin-3c isoform and is translated into a polyglutamine stretch, a feature common to all known CAG repeat disorders. Ataxin-3 like immunoreactivity was observed in all human brain regions and peripheral organs studied. In neuronal cells of control individuals, ataxin-3c was expressed cytoplasmatically and had a somatodendritic and axonal distribution. In SCA3 patients, however, C-terminal ataxin-3c antibodies as well as anti-ataxin-3 monoclonal antibodies (1 H9) and anti-ubiquitin antibodies detected intranuclear inclusions (NIs) in neuronal cells of affected brain regions. A monoclonal antibody, 2B6, directed against an internal part of the protein, barely detected these NIs implying proteolytic cleavage of ataxin-3 prior to its transport into the nucleus. These findings provide evidence that the alternate isoform of ataxin-3 is involved in the pathogenesis of SCA3/MJD. Intranuclear protein aggregates appear as a common feature of neurodegenerative polyglutamine disorders.

Amino Acid Sequence↗

PubMedDate not supplied

Phenotypic effects of expanded ataxin-1 polyglutamines with interruptions in vitro.

Spinocerebellar ataxia type 1 is a neurodegenerative disease caused by expansion of an uninterrupted glutamine repeat in ataxin-1 protein. Protein aggregation and immunoreactivity to 1C2 monoclonal antibody are two distinct pathognomonic features of expanded ataxin-1, as well as of other polyglutamine disorders. Rare cases of non-affected elderly subjects carrying expanded ataxin-1 alleles were found in random population. However, in these alleles the glutamine stretch was interrupted by histidines. Due to lack of phenotype, these alleles should be considered "normal". Most importantly, occurrence of these unusual alleles provides a unique opportunity to investigate which molecular properties of expanded ataxin-1 are not coupled to polyglutamine pathogenesis. Towards this goal, we compared in vitro the immunoreactivity to 1C2 antibody and the ability to form aggregates of interrupted and uninterrupted alleles. Immunoblotting showed that expanded-interrupted ataxin-1 had an affinity to 1C2 resembling that of normal ataxin-1. On the contrary, filter assay showed that aggregation rate of expanded-interrupted ataxin-1 resembles that of expanded-uninterrupted ataxin-1. These observations indicate that affinity for 1C2 does not directly correlate with self-aggregation of ataxin-1. Moreover, self-aggregation is not directly affected by histidine interruptions. In conclusion, these results support the hypothesis that mechanisms underlying neuronal degeneration are triggered by protein misfolding rather than by protein aggregation.

Amyloidosis↗

PubMed2003

Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice.

Polyglutamine-induced neurodegeneration in transgenic mice carrying the spinocerebellar ataxia type 1 (SCA1) gene is modulated by subcellular distribution of ataxin-1 and by components of the protein folding/degradation machinery. Since phosphorylation is a prominent mechanism by which these processes are regulated, we examined phosphorylation of ataxin-1 and found that serine 776 (S776) was phosphorylated. Residue 776 appeared to affect cellular deposition of ataxin-1[82Q] in that ataxin-1[82Q]-A776 failed to form nuclear inclusions in tissue culture cells. The importance of S776 for polyglutamine-induced pathogenesis was examined by generating ataxin-1[82Q]-A776 transgenic mice. These mice expressed ataxin-1[82Q]-A776 within Purkinje cell nuclei, yet the ability of ataxin-1[82Q]-A776 to induce disease was substantially reduced. These studies demonstrate that polyglutamine tract expansion and localization of ataxin-1 to the nucleus of Purkinje cells are not sufficient to induce disease. We suggest that S776 of ataxin-1 also has a critical role in SCA1 pathogenesis.

Amino Acid Sequence↗

PubMed1999

Expression of ataxin-2 in brains from normal individuals and patients with Alzheimer's disease and spinocerebellar ataxia 2.

Spinocerebellar ataxia type 2 (SCA2) is caused by expansion of a CAG trinucleotide repeat located in the coding region of the human SCA2 gene. The SCA2 gene product, ataxin-2, is a basic protein with two domains (Sm1 and Sm2) implicated in RNA splicing and protein interaction. However, the wild-type function of ataxin-2 is yet to be determined. To help clarify the function of ataxin-2, we produced antibodies to three antigenic peptides of ataxin-2 and analyzed the expression pattern of ataxin-2 in normal and SCA2 adult brains and cerebellum at different developmental stages. These studies revealed that (1) both wild-type and mutant forms of ataxin-2 were synthesized; (2) the wild-type ataxin-2 was localized in the cytoplasm in specific neuronal groups with strong labeling of Purkinje cells; (3) the level of ataxin-2 increased with age in Purkinje cells of normal individuals; and (4) ataxin-2-like immunoreactivity in SCA2 brain tissues was more intense than in normal brain tissues, and intranuclear ubiquitinated inclusions were not seen in SCA2 brain tissues.

Adult↗

PubMed2002

Expression of ataxin-7 in CNS and non-CNS tissue of normal and SCA7 individuals.

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder primarily affecting the cerebellum, brain stem and retina. The disease is caused by an expanded polyglutamine tract in the protein ataxin-7. In this study we analyzed the expression pattern of ataxin-7 in CNS and non-CNS tissue from three SCA7 patients and age-matched controls. SCA7 is a rare autosomal dominant disorder, limiting the number of patients available for analysis. We therefore compiled data on ataxin-7 expression from all SCA7 patients (n=5) and controls (n=7) published to date, and compared with the results obtained in this study. Expression of ataxin-7 was found in neurons throughout the CNS and was highly abundant in Purkinje cells of the cerebellum, in regions of the hippocampus and in cerebral cortex. Ataxin-7 expression was not restricted to regions of pathology, and there were no apparent regional differences in ataxin-7 expression patterns between patients and controls. The subcellular distribution of ataxin-7 was primarily nuclear in all brain regions studied. In cerebellar Purkinje cells, however, differences in subcellular distribution of ataxin-7 were observed between patients and controls of different ages. Here we provide an increased understanding of the distribution of ataxin-7, and the possible implication of subcellular localization of this protein on disease pathology is discussed.

Adult↗

PubMed2000

Conserved phosphoprotein interaction motif is functionally interchangeable between ataxin-7 and arrestins.

Olivopontocerebellar atrophy with retinal degeneration is a hereditary neurodegenerative disorder that belongs to the subtype II of the autosomal dominant cerebellar ataxias and is characterized by early-onset cerebellar and macular degeneration preceded by diagnostically useful tritan colorblindness. The gene mutated in the disease (SCA7) has been mapped to chromosome 3p12-13.5, and positional cloning identified the cause of the disease as CAG repeat expansion in this gene. The SCA7 gene product, ataxin-7, is an 897 amino acid protein with an expandable polyglutamine tract close to its N-terminus. No clues to ataxin-7 function have been obtained from sequence database searches. Here we report that ataxin-7 has a motif of ca. 50 amino acids, related to the phosphate-binding site of arrestins. To test the relevance of this sequence similarity, we introduced the putative ataxin-7 phosphate-binding site into visual arrestin and beta-arrestin. Both chimeric arrestins retain receptor-binding affinity and show characteristic high selectivity for phosphorylated activated forms of rhodopsin and beta-adrenergic receptor, respectively. Although the insertion of a Gly residue (absent in arrestins but present in the putative phosphate-binding site of ataxin-7) disrupts the function of visual arrestin-ataxin-7 chimera, it enhances the function of beta-arrestin-ataxin-7 chimera. Taken together, our data suggest that the arrestin-like site in the ataxin-7 sequence is a functional phosphate-binding site. The presence of the phosphate-binding site in ataxin-7 suggests that this protein may be involved in phosphorylation-dependent binding to its protein partner(s) in the cell.

Amino Acid Sequence↗

PubMed2003

Expansion of the polyQ repeat in ataxin-2 alters its Golgi localization, disrupts the Golgi complex and causes cell death.

Spinocerebellar ataxia type 2 (SCA2) is caused by the expansion of a polyglutamine (polyQ) repeat in ataxin-2, the SCA2 gene product. In contrast to other polyQ diseases, intranuclear inclusions are not prominent in SCA2. In animal models with expression of mutant ataxin-2 targeted to Purkinje cells, neuronal dysfunction and morphologic changes are observed without the formation of intranuclear aggregates. In this report, we investigated the mechanisms underlying SCA2 pathogenesis using cellular models. We confirmed that the SCA2 gene product, ataxin-2, was predominantly located in the Golgi apparatus. Deletion of ER-exit and trans-Golgi signals in ataxin-2 resulted in an altered subcellular distribution. Expression of full-length ataxin-2 with an expanded repeat disrupted the normal morphology of the Golgi complex and colocalization with Golgi markers was lost. Intranuclear inclusions were only seen when the polyQ repeat was expanded to 104 glutamines, and even then were only observed in a small minority of cells. Expression of ataxin-2 with expanded repeats in PC12 and COS1 cells increased cell death compared with normal ataxin-2 and elevated the levels of activated caspase-3 and TUNEL-positive cells. These results suggest a link between cell death mediated by mutant ataxin-2 and the stability of the Golgi complex. The formation of intranuclear aggregates is not necessary for in vitro cell death caused by expression of full-length mutant ataxin-2.

Animals↗

PubMed2000

Relationship between ataxin-1 nuclear inclusions and Purkinje cell specific proteins in SCA-1 transgenic mice.

Spinocerebellar ataxia-1 (SCA-1), like other polyglutamine diseases, is associated with aggregation of mutant protein ataxin-1 in the nuclei of susceptible neurons. The role of ataxin-1 aggregates in the pathogenesis of susceptible neurons, especially cerebellar Purkinje cells, is unknown. The present study was initiated to determine the temporal relationship between ataxin-1 aggregation and the sequence of specific biochemical changes in Purkinje cells in SCA-1 transgenic mice (TM). Earlier, we demonstrated that SCA-1 TM with no Purkinje cell loss and no alterations in home cage behavior show decreased expression of calcium-binding proteins calbindin-D28k (CaB) and parvalbumin (PV) in Purkinje cells. To determine if increased expression of mutant ataxin-1 in TM is also associated with earlier biochemical changes in Purkinje cells, both heterozygous and homozygous (B05 line of SCA-1) TM were used. The age of onset of ataxia in SCA-1 TM was at 12 weeks in heterozygotes and 6 weeks in homozygotes. In 6 week old heterozygous TM, Western blot analysis of growth associated protein 43 (GAP-43) and synaptophysin revealed no significant alterations as compared with the age-matched nontransgenic mice (nTM), whereas CaB was significantly reduced. beta-III-Tubulin was used as a specific Purkinje cell marker protein, immunohistochemical localization showed strong beta-III-tubulin immunoreactivity (IR) in Purkinje cells in 6 week old heterozygous TM, whereas CaB and PV IR were markedly reduced in the same neurons (double immunofluorescence staining). Most Purkinje cells from heterozygous (12 weeks old) and homozygous (6 weeks old) TM contained ataxin-1 nuclear inclusions (NIs). Cells with and without visible NIs revealed reduced PV and CaB IR; however, the changes were overtly more severe in cells with visible NIs. In contrast, the same cells were strongly immunoreactive to beta-III-tubulin. CaB, which is also present in the nucleus, colocalized with ataxin-1 and ubiquitin positive NIs. Further, RT-PCR analysis of CaB mRNA in the cerebellum in 6 week old heterozygous TM demonstrated a significant decrease in mRNA in comparison with the aged-matched nTM. These data suggest that there are selective alterations in the expression of CaB and PV in Purkinje cells which possibly occur earlier than ataxin-1 aggregation. Further, we speculate that ataxin-1 aggregates may not be toxic in general; however, they may deplete specific proteins essential for Purkinje cell viability in SCA-1 TM.

Animals↗

PubMed2003

p80 coilin, a coiled body-specific protein, interacts with ataxin-1, the SCA1 gene product.

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.

Animals↗

PubMed1998

Heterogeneous intracellular localization and expression of ataxin-3.

Spinocerebellar ataxia type 3 or Machado-Joseph disease (SCA3/MJD) is an autosomal dominant neurodegenerative disorder caused by an unstable and expanded CAG trinucleotide repeat that leads to the expansion of a polyglutamine tract in a protein of unknown function, ataxin-3. We have generated and characterized a panel of monoclonal and polyclonal antibodies raised against ataxin-3 and used them to analyze its expression and localization. In Hela cells, multiple isoforms are expressed besides the major 55-kDa form. While the majority of ataxin-3 is cytosolic, both immunocytofluorescence and subcellular fractionation studies indicate the presence of ataxin-3, in particular, of some of the minor isoforms, in the nuclear and mitochodrial compartments. We also show that ataxin-3 can be phosphorylated. In the brain, only one ataxin-3 isoform containing the polyglutamine stretch was detected, and normal and mutated proteins were found equally expressed in all patient brain regions analyzed. In most neurons, ataxin-3 had a cytoplasmic, dendritic, and axonal localization. Some neurons presented an additional nuclear localization. Ataxin-3 is widely expressed throughout the brain, with a variable intensity specific for subpopulations of neurons. Its expression is, however, not restricted to regions that show intranuclear inclusions and neurodegeneration in SCA3/MJD.

Amino Acid Sequence↗

PubMed2001

Ataxin-7 interacts with a Cbl-associated protein that it recruits into neuronal intranuclear inclusions.

Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease caused by expansion of a CAG repeat in the coding region of the SCA7 gene. The disease primarily affects the cerebellum and the retina, but also many other central nervous system (CNS) structures as the disease progresses. Ataxin-7, encoded by the SCA7 gene, is a protein of unknown function expressed in many tissues including the CNS. In normal brain, ataxin-7 is found in the cytoplasm and/or nucleus of neurons, but in SCA7 brain ataxin-7 accumulates in intranuclear inclusions. Ataxin-7 is expressed ubiquitously, but mutation leads to neuronal death in only certain areas of the brain. This selective pattern of degeneration might be explained by interaction with a partner that is specifically expressed in vulnerable cells. We used a two-hybrid approach to screen a human retina cDNA library for ataxin-7-binding proteins, and isolated R85, a splice variant of Cbl-associated protein (CAP). R85 and CAP are generated by alternative splicing of the gene SH3P12 which we localized on chromosome 10q23-q24. The interaction between ataxin-7 and the SH3P12 gene products (SH3P12GPs) was confirmed by pull-down and co-immunoprecipitation. SH3P12GPs are expressed in Purkinje cells in the cerebellum. Ataxin-7 colocalizes with full-length R85 (R85FL) in co-transfected Cos-7 cells and with one of the SH3P12GPs in neuronal intranuclear inclusions in brain from a SCA7 patient. We propose that this interaction is part of a physiological pathway related to the function or turnover of ataxin-7. Its role in the pathophysiological process of SCA7 disease is discussed.

Alternative Splicing↗