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G Yvert

Publications and source records attributed to G Yvert.

10 recordsLinked to original sources
PubMed2001

SCA7 mouse models show selective stabilization of mutant ataxin-7 and similar cellular responses in different neuronal cell types.

Accumulation of expanded polyglutamine proteins and selective pattern of neuronal loss are hallmarks of at least eight neurodegenerative disorders, including spinocerebellar ataxia type 7 (SCA7). We previously described SCA7 mice displaying neurodegeneration with progressive ataxin-7 accumulation in two cell types affected in the human pathology. We describe here a new transgenic model with a more widespread expression of mutant ataxin-7, including neuronal cell types unaffected in SCA7. In these mice a similar handling of mutant ataxin-7, including a cytoplasm to nucleus translocation and accumulation of N-terminal fragments, was observed in all neuronal populations studied. An extensive screen for chaperones, proteasomal subunits and transcription factors sequestered in nuclear inclusions (NIs) disclosed no pattern unique to neurons undergoing degeneration in SCA7. In particular, we found that the mouse TAF(II)30 subunit of the TFIID initiation complex is markedly accumulated in NIs, even though this protein does not contain a polyglutamine stretch. A striking discrepancy between mRNA and ataxin-7 levels in transgenic mice expressing the wild-type protein but not in those expressing the mutant one, indicates a selective stabilization of mutant ataxin-7, both in this model and the P7E/N model described previously. These mice therefore provide in vivo evidence that the polyglutamine expansion mutation can stabilize its target protein.

Animals↗
PubMed2000

Expanded polyglutamines induce neurodegeneration and trans-neuronal alterations in cerebellum and retina of SCA7 transgenic mice.

Among the eight progressive neurodegenerative diseases caused by polyglutamine expansions, spinocerebellar ataxia type 7 (SCA7) is the only one to display degeneration in both brain and retina. We show here that mice overexpressing full-length mutant ataxin-7[Q90] either in Purkinje cells or in rod photoreceptors have deficiencies in motor coordination and vision, respectively. In both models, although with different time courses, an N-terminal fragment of mutant ataxin-7 accumulates into ubiquitinated nuclear inclusions that recruit a distinct set of chaperone/proteasome subunits. A severe degeneration is caused by overexpression of ataxin-7[Q90] in rods, whereas a similar overexpression of normal ataxin-7[Q10] has no obvious effect. The degenerative process is not limited to photoreceptors, showing secondary alterations of post-synaptic neurons. These findings suggest that proteolytic cleavage of mutant ataxin-7 and trans-neuronal responses are implicated in the pathogenesis of SCA7.

Animals↗
PubMed2000

Distribution of ataxin-7 in normal human brain and retina.

Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease caused by the expansion of a CAG repeat encoding a polyglutamine tract in the protein ataxin-7. We developed antibodies directed against two different parts of the ataxin-7 protein and studied its distribution in brain and peripheral tissue from healthy subjects. Normal ataxin-7 was widely expressed in brain, retina and peripheral tissues, including striated muscle, testis and thyroid gland. In the brain, expression of ataxin-7 was not limited to areas in which neurones degenerate, and the level of expression was not related to the severity of neuronal loss. Immunoreactivity was low in some vulnerable populations of neurones, such as Purkinje cells. In neurones, ataxin-7 was found in the cell bodies and in processes. Nuclear labelling was also observed in some neurones, but was not related to the distribution of intranuclear inclusions observed in an SCA7 patient. In this patient, the proportion of neurones with nuclear labelling was higher, on average, in regions with neuronal loss. Double immunolabelling coupled with confocal microscopy showed that ataxin-7 colocalized with BiP, a marker of the endoplasmic reticulum, but not with markers of mitochondria or the trans-Golgi network.

Adult↗
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↗
PubMed1998

The human small conductance calcium-regulated potassium channel gene (hSKCa3) contains two CAG repeats in exon 1, is on chromosome 1q21.3, and shows a possible association with schizophrenia.

Mutations in various ion channel genes are responsible for neuromuscular and other neurological disorders. We have previously identified the human small conductance calcium-activated potassium channel gene (hSKCa3) which has two tandemly arranged CAG repeats in its 5' region. Here we have isolated the first genomic clones containing the gene and have shown that both repeats are in exon 1. Homology to the previously localized sequence tagged site G16005 indicated that the gene may be on chromosome 22q, however using polymerase chain reaction amplification of somatic cell hybrid DNA and fluorescence in situ hybridization of two P1 artificial chromosome clones, we physically localized the gene to chromosome 1q21.3. We previously found an association between the highly polymorphic second (more 3') CAG repeat and schizophrenia in 98 patients and 117 controls. We have now genotyped an additional 19 patients with schizophrenia and have performed statistical analyses on the entire group of patients and controls to investigate the possible effect of age of onset, family history, and gender of the patients on the observed association. None of these factors were found to influence the results. Both CAG repeats have been typed in 86 bipolar I disorder patients, and no significant difference in allele distribution was observed between our bipolar disorder patients and controls.

Animals↗
PubMed1997

Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion.

The gene for spinocerebellar ataxia 7 (SCA7) has been mapped to chromosome 3p12-13. By positional cloning, we have identified a new gene of unknown function containing a CAG repeat that is expanded in SCA7 patients. On mutated alleles, CAG repeat size is highly variable, ranging from 38 to 130 repeats, whereas on normal alleles it ranges from 7 to 17 repeats. Gonadal instability in SCA7 is greater than that observed in any of the seven known neuro-degenerative diseases caused by translated CAG repeat expansions, and is markedly associated with paternal transmissions. SCA7 is the first such disorder in which the degenerative process also affects the retina.

Adult↗
PubMed1997

Molecular and clinical correlations in spinocerebellar ataxia 2: a study of 32 families.

Spinocerebellar ataxia 2 (SCA2) is caused by the expansion of an unstable CAG repeat encoding a polyglutamine tract. One hundred and eighty four index patients with autosomal dominant cerebellar ataxia type I were screened for this mutation. We found expansion in 109 patients from 30 families of different geographical origins (15%) and in two isolated cases with no known family histories (2%). The SCA2 chromosomes contained from 34 to 57 repeats and consisted of a pure stretch of CAG, whereas all tested normal chromosomes (14-31 repeats), except one with 14 repeats, were interrupted by 1-3 repeats of CAA. As in other diseases caused by unstable mutations, a strong negative correlation was observed between the age at onset and the size of the CAG repeat (r = -0.81). The frequency of several clinical signs such as myoclonus, dystonia and myokymia increased with the number of CAG repeats whereas the frequency of others was related to disease duration. The CAG repeat was highly unstable during transmission with variations ranging from -8 to +12, and a mean increase of +2.2, but there was no significant difference according to the parental sex. This instability was confirmed by the high degree of gonadal mosaicism observed in sperm DNA of one patient.

Adolescent↗
PubMed1996

Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats.

Two forms of the neurodegenerative disorder spinocerebellar ataxia are known to be caused by the expansion of a CAG (polyglutamine) trinucleotide repeat. By screening cDNA expression libraries, using an antibody specific for polyglutamine repeats, we identified six novel genes containing CAG stretches. One of them is mutated in patients with spinocerebellar ataxia linked to chromosome 12q (SCA2). This gene shows ubiquitous expression and encodes a protein of unknown function. Normal SCA2 alleles (17 to 29 CAG repeats) contain one to three CAAs in the repeat. Mutated alleles (37 to 50 repeats) appear particularly unstable, upon both paternal and maternal transmissions. The sequence of three of them revealed pure CAG stretches. The steep inverse correlation between age of onset and CAG number suggests a higher sensitivity to polyglutamine length than in the other polyglutamine expansion diseases.

Adolescent↗