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At least 19 recordsLinked to original sources
PubMed2026

Importin-8 silencing reduces Ataxin-3 aggregation and alleviates Machado-Joseph disease/spinocerebellar ataxia type 3.

Machado-Joseph disease (MJD) is a polyglutamine neurodegenerative disorder characterized by the formation of neuronal intranuclear Ataxin-3 inclusions. The nucleocytoplasmic transport is known to be profoundly dysregulated from early stages of neurodegeneration, further aggravating its progressive nature. To understand the contribution of these proteins in MJD, we screened the effect of 34 transport proteins on Ataxin-3 aggregation. Importin-8 (Ipo8 gene) was selected for further neuropathology and behavior analysis to evaluate its modulatory effect in vitro and in vivo. Our results showed that Ipo8 mRNA expression is increased in MJD and that, upon Ipo8 downregulation, Ataxin-3 aggregation and neuronal dysfunction are reduced in vitro and in vivo. Furthermore, Ipo8 silencing was demonstrated to alleviate ataxic traits in vivo. Collectively, our findings indicate that Importin-8 may exert its protective effect by modulating NF-kb/p65 and Argonaute-2 proteins, also previously linked to MJD, standing as a promising therapeutic target to delay disease progression.

Argonaute-2↗
PubMed1997

Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain.

Machado-Joseph disease (MJD) is one of at least six neurodegenerative diseases caused by expansion of a CAG repeat encoding a polyglutamine tract in the disease protein. To study the molecular mechanism of disease, we isolated both normal and expanded repeat MJD1 cDNAs, and generated antiserum against the recombinant gene product, called ataxin-3. Using this antiserum, we demonstrate that in disease tissue, both the normal and mutant ataxin-3 protein are expressed throughout the body and in all regions of the brain examined, including areas generally spared by disease. In brain, certain regions (the striatum, for example) express ataxin-3 in only a limited subset of neurons. Immunolocalization studies in normal and disease brain, and in transfected cells, indicate that ataxin-3 is predominantly a cytoplasmic protein that localizes to neuronal processes as well. We conclude that in MJD, as in other polyglutamine repeat diseases, cellular expression of the disease gene is not itself sufficient to cause neuronal degeneration; other cell-specific factors must be invoked to explain the restricted neuropathology seen in MJD. The restricted expression of ataxin-3 in certain regions, however, may influence the pattern of neurodegeneration and provide clues to the protein's function.

Adult↗
PubMed2026

Extracellular vesicles-mediated delivery of SpCas9 RNPs for therapeutic gene editing in Spinocerebellar Ataxia Type 3.

Spinocerebellar Ataxia Type 3 (SCA3) is a neurodegenerative dominantly-inherited disorder caused by an overexpansion of a CAG tract within the ATXN3 gene, conferring toxic properties to the ataxin-3 protein. Genome editing with CRISPR-Cas9 enzymes is a promising strategy to inactivate mutant ATXN3 alleles, however, in vivo delivery remains challenging. Extracellular vesicles (EVs) are promising delivery vehicles for Cas9 and single guide RNA (sgRNA) ribonucleoproteins that minimize genomic exposure to highly active endonucleases. In this study, we designed SpCas9 with a palmitoylation motif that enables SpCas9 and sgRNA enrichment into EVs. Introduction of a photocleavable linker - PhoCl - allowed the photo-inducible release of SpCas9 from the palmitoylation motif in EVs, increasing target engagement to ATXN3 in vitro. EVs loaded with SpCas9 ribonucleoproteins resulted in ATXN3 knockout in SCA3 patient-derived iPSCs and two SCA3 animal models. These findings highlight an innovative route for transient delivery of gene editing tools. This approach provides a promising therapeutic platform for the treatment of genetic diseases, including SCA3.

Humans↗
PubMed1996

Strong linkage disequilibrium and haplotype analysis in Japanese pedigrees with Machado-Joseph disease.

To identify the markers tightly linked to Machado-Joseph disease (MJD) and to investigate whether a limited number of ancestral chromosomes are shared by Japanese MJD pedigrees, a detailed linkage analysis employing D14S55, D14S48, D14S67, D14S291, D14S280, AFM343vf1, D14S81, D14S265, D14S62, and D14S65 was performed. The results of multipoint linkage analysis as well as detection of critical recombination events indicate that the gene for MJD is localized in a 4-cM region between D14S280-D14S81. We found strong linkage disequilibria at AFM343vf1 and D14S81, and association of a few common haplotypes with MJD. These results indicate that there is an obvious founder effect in Japanese MJD and suggest the possibility of the existence of predisposing haplotypes which are prone to expansions of CAG repeats.

Ataxin-3↗
PubMed1996

Electrophysiological findings in a Danish family with Machado-Joseph disease.

Machado-Joseph disease (MJD) is a neurodegenerative disorder with autosomal dominant inheritance, We have carried out electrophysiological studies in 8 individuals belonging to a Danish family with several affected members. Five had an expanded trinucleotide (CAG) repeat sequence in the MJD1 gene on chromosome 14 indicating MJD, while 3 unaffected individuals had normal repeat lengths. Three individuals with repeat expansion had clinical symptoms and signs of the Machado or "type III" phenotype, whereas 2 had slight symptoms and signs only, Electrophysiological evaluation included visual, somatosensory, and auditory brain stem evoked potentials, quantitative electromyography, and nerve conduction studies. In the patients with clinical MJD, evoked potential studies showed multimodal abnormalities, electromyography showed neurogenic changes, and nerve conduction studies showed signs of severe loss of motor and sensory nerve fibers. Of the 2 patients with slight symptoms and signs, 1 had evidence of peripheral and central affection, while the other had slight signs of a central affection. This study provides insight into the distribution and character of electrophysiological abnormalities in MJD of putative importance for an understanding of the pathogenesis of the disease, and for monitoring disease progress, or the outcome of a possible treatment.

Adult↗
PubMed1996

Regional and cellular expression of the Machado-Joseph disease gene in brains of normal and affected individuals.

Machado-Joseph disease (MJD) is an autosomal dominant disorder characterized pathologically by spinocerebellar degeneration. Recently, an expansion of CAG repeat in a gene located at the chromosome 14q32.1 was found to be responsible for the disease. Here, we investigated in situ the expression of the MJD gene (MJD1) in the central nervous systems of normal and affected individuals and in rat brains. This gene was expressed in all regions of rat and human normal brains with certain regional variations. MJD1 was transcribed preferentially in neurons, although low levels of MJD1 mRNA were also observed in glial cells. Neurons susceptible to degeneration in MJD expressed MJD1 but not selectively. In the affected brains, the MJD1 mRNA distribution and amount in all the areas examined were similar in patients and controls. In addition, the cellular MJD1 mRNA level correlated neither with clinical severity nor expanded length. Our study showed that the expression levels of trinucleotide repeats in MJD patients and normal controls did not differ, indicating that the pathogenesis of MJD may involve direct toxicity to vulnerable subsets and/or region-specific cofactors of MJD proteins.

Adolescent↗
PubMed1997

Machado-Joseph disease gene product identified in lymphocytes and brain.

Machado-Joseph disease (MJD) is associated with the expansion of an unstable CAG repeat. The existence of an abnormal gene product in MJD was previously suggested with the expanded polyglutamine stretch-specific antibody. However, the product of the normal allele has not previously been identified. We generated monoclonal antibodies against the fusion protein (codon 225-310) of the MJD gene product and then identified the MJD1 gene product in normal lymphoblastoid cells as a approximately 50-kDa protein by immunoblot analysis. The electrophoretic mobility differences among the normal allele products corresponds to the molecular size difference produced by the polyglutamine stretch and the polymorphism at the C-terminus. Moreover, abnormal immunoreactive bands which were larger than the normal ones were found as a approximately 60-kDa protein exclusively in the MJD samples. The cytoplasm and the nuclei of neurons and glial cells were stained by these antibodies with immunocytochemistry. As in other CAG repeat diseases, the abnormal and normal allele products were almost equally expressed in lymphoblastoid cells and the brain of MJD patients.

Alleles↗
PubMed1996

Linkage disequilibrium analysis in Machado-Joseph disease patients of different ethnic origins.

Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration originally described in families of Portuguese-Azorean ancestry. The hypothesis that its present world distribution could result from the spread of an original founder mutation has been raised. To test this possibility we have conducted a linkage disequilibrium study of markers segregating with the MJD1 locus in a total of 64 unrelated families of different geographical origins. Significant association was detected between the MJD1 locus and marker alleles at loci D14S280, D14S1050 and D14S81. All affected individuals, except one Chinese family, had allele 3 (237 bp) at D14S280. This finding is consistent with a founder effect in our MJD population. However, distinct haplotypes were observed in patients originating from the two Azorean islands showing the highest disease prevalence; therefore, the possible existence of more than one founder mutation can not be excluded with the markers currently available.

Alleles↗
PubMed1997

Machado-Joseph disease gene products carrying different carboxyl termini.

Three cDNA clones for the Machado-Joseph disease gene (MJD1) were isolated, two of which have a new exon sequence and a distinct 3' terminal nucleotide sequence resulting in a new carboxyl terminal domain in the translated product. The nucleotide sequence of the other one is similar to the previously published one except for five polymorphisms, one of which is a single nucleotide substitution resulting in a change from the stop codon (TAA; allele A) to a tyrosine residue (TAC; allele C). Genetic analysis results suggest that Japanese MJD mutations are associated with allele A.

Amino Acid Sequence↗
PubMed1996

Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo.

Recently, we identified a novel gene, MJD1, which contains an expanded CAG triplet repeat in Machado-Joseph disease. Here we report the induction of apoptosis in cultured cells expressing a portion of the MJD1 gene that includes the expanded CAG repeats. Cell death occurs only when the CAG repeat is translated into polyglutamine residues, which apparently precipitate in large covalently modified forms. We also created ataxic transgenic mice by expressing the expanded polyglutamine stretch in Purkinje cells. Our results demonstrate the potential involvement of the expanded polyglutamine as the common aetiological agent for inherited neurodegenerative diseases with CAG expansions.

Animals↗
PubMed1994

CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1.

We have identified a novel gene containing CAG repeats and mapped it to chromosome 14q32.1, the genetic locus for Machado-Joseph disease (MJD). In normal individuals the gene contains between 13 and 36 CAG repeats, whereas most of the clinically diagnosed patients and all of the affected members of a family with the clinical and pathological diagnosis of MJD show expansion of the repeat-number (from 68-79). Southern blot analyses and genomic cloning demonstrates the existence of related genes. These results raise the possibility that similar abnormalities in related genes may give rise to diseases similar to MJD.

Adult↗
PubMed1995

Trinucleotide expansion within the MJD1 gene presents clinically as spinocerebellar ataxia and occurs most frequently in German SCA patients.

Autosomal dominant spinocerebellar ataxia (SCA) is a clinically and genetically heterogeneous neurodegenerative disorder which leads to progressive cerebellar ataxia. A gene responsible for SCA type 3 has been mapped to human chromosome 14q, close to the Machado-Joseph disease (MJD) locus. The MJD1 gene has recently been cloned and the disease causing mutation has been identified as an unstable and expanded (CAG)n trinucleotide repeat. As some clinical features of MJD overlap with those of SCA we investigated the MJD mutation in 38 German families with dominantly inherited SCA. The MJD1 (CAG)n expansion was identified in 19 families. In contrast, the trinucleotide expansion was not observed in 21 ataxia patients without family history of the disease. Analysis of the (CAG)n repeat length in 30 patients revealed an inverse correlation with the age of onset. The (CAG)n stretch of the affected allele varied between 67 and 78 trinucleotide units, the normal alleles carried between 12 and 28 simple repeats. These results demonstrate that the MJD mutation causes the disease phenotype of most SCA patients in Germany.

Age of Onset↗
PubMed1995

Evidence for inter-generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease.

The size of the (CAG)n repeat array in the 3' end of the MJD1 gene and the haplotype at a series of microsatellite markers surrounding the MJD1 gene were examined in a large cohort of Japanese and Caucasian subjects affected with Machado-Joseph disease (MJD). Our data provide five novel observations. First, MJD is associated with expansion fo the array from the normal range of 14-37 repeats to 68-84 repeats in most Japanese and Caucasian subjects, but no subjects were observed with expansions intermediate in size between those of the normal and MJD affected groups. Second, the expanded allele associated with MJD displays inter-generational instability, particularly in male meioses, and this instability was associated with the clinical phenomenon of anticipation. Third, the size of the expanded allele is not only inversely correlated with the age-of-onset of MJD (r = -0.738, p < 0.001), but is also correlated with the frequency of other clinical features [e.g. pseudoexophthalmos and pyramidal signs were more frequent in subjects with large repeats (p < 0.001 and p < 0.05 respectively)]. Fourth, the disease phenotype is significantly more severe and had an early age of onset (16 years) in a subject homozygous for the expanded allele, which contrasts with Huntington disease and suggests that the expanded allele in the MJD1 gene could exert its effect either by a dominant negative effect (putatively excluded in HD) or by a gain of function effect as proposed for HD. Finally, Japanese and Caucasian subjects affected with MJD share haplotypes at several markers surrounding the MJD1 gene, which are uncommon in the normal Japanese and Caucasian population, and which suggests the existence either of common founders in these populations or of chromosomes susceptible to pathologic expansion of the CAG repeat in the MJD1 gene.

Age of Onset↗
PubMed1996

Analysis of CAG repeat of the Machado-Joseph gene in human, chimpanzee and monkey populations: a variant nucleotide is associated with the number of CAG repeats.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder associated with an unstable and expanded CAG repeat. We analyzed this locus from various sources including MJD families, Acadian, African American, Caucasian, Greenland Inuit and Thai populations. The range of the CAG repeat size was 14-40 in the normal alleles while the MJD alleles contained 73-78 repeats in our studies. We found 25 different alleles on normal chromosomes with a heterozygosity of 0.86 in combined populations. The most common alleles were 23 (22.9%) and 14 (25.5%) repeats. We also examined 16 chimpanzees and various Old World monkeys: a pigtail macaque, a mangabey and 12 rhesus macaques. The DNA sequences surrounding the CAG repeat did not vary among species. The range of the number of the CAG repeats is 13-14 in macaques, 16 in mangabey and 14-20 in chimpanzees. Variant CAA or AAG triplets in the CAG repeat tracts were found in all 268 human, 28 monkey and 32 chimpanzee chromosomes. As reported in a previous study [Kawaguchi et al. (1994) Nature Genet. 8, 221-228] the common variant positions were the third (CAA), fourth (AAG) and sixth (CAA) positions. However, we found three human chromosomes containing CAG at the sixth position and the mangabey had AAG at the ninth position. In addition, we found CAG at the fourth position and AAG at the sixth position in all macaque chromosomes. The nucleotide following the CAG repeat tract was usually G in all species studied. However, we sometimes found C at this position in human and chimpanzee chromosomes. Interestingly, this variant C was found in all expanded chromosomes and in 54.5% of chromosomes with 27-40 CAG repeats but it was not found in any chromosomes with less than 20 CAG repeats. We hypothesize that the variant C may be associated with CAG repeat instability.

Animals↗
PubMed1997

Single sperm analysis of the CAG repeats in the gene for Machado-Joseph disease (MJD1): evidence for non-Mendelian transmission of the MJD1 gene and for the effect of the intragenic CGG/GGG polymorphism on the intergenerational instability.

To investigate the mechanism of the meiotic instability of expanded CAG repeats in the gene for Machado-Joseph disease (MJD1), we analyzed the CAG repeat sizes of 1036 single sperm from six individuals with Machado-Joseph disease (MJD). The segregation ratio between single sperm with an expanded allele and those with a normal allele is significantly different (P <0.0001) from the expected 1:1 segregation ratio, which demonstrates segregation distortion of expanded alleles in male meiosis. In single sperm from individuals with the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] genotype, significantly greater instability of the CAG repeat was observed compared with single sperm from individuals with the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] genotype (F-test, P <0.001). These findings in single sperm confirm non-Mendelian transmission of the MJD1 gene and the effect of the intragenic CGG/GGG polymorphism on the intergenerational instability of the CAG repeats in the MJD1 gene, which have been observed in clinical and genetic studies. Our results indicate similarities and dissimilarities between MJD and Huntington's disease or myotonic dystrophy in terms of the inter-allelic interaction, segregation distortions and size distribution of trinucleotide repeats in mutant alleles. Further study is required to determine whether there is a common mechanism underlying the instability of the triplet repeats in 'triplet repeat diseases'.

Alleles↗