The genomic structure and expression of MJD, the Machado-Joseph disease gene

Ichikawa, Yaeko; Goto, Jun; Hattori, Masahira; Toyoda, Atsushi; Ishii, Kazuo; Jeong, Seon-Yong; Hashida, Hideji; Masuda, Naoki; Ogata, Katsuhisa; Kasai, Fumie; Hirai, Momoki; Maciel, Patrı́cia; Rouleau, Guy A.; Sakaki, Yoshiyuki; Kanazawa, Ichiro

doi:10.1007/s100380170060

Cited by 68 publications

(73 citation statements)

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“…both the number and the sizes of exons and introns-11 exons and 10 introns-are identical [7]. The Mjd gene contains a CAG repeat localized in exon 10, as occurs in the human gene.…”

Section: Discussionmentioning

confidence: 99%

“…Mouse ataxin-3 seemed to be ubiquitously distributed and to have a cytoplasmic localization, as evidenced in immunostained sections (Figs. 6,7,and 8). The protein was highly expressed in skeletal, cardiac, and smooth muscle (Figs.…”

Section: Cihr Author Manuscriptmentioning

confidence: 99%

“…Alternative splicing of MJD results in the production of different isoforms of ataxin-3 [8], which are expressed in various tissues and have been detected both in the nucleus and in the cytoplasm [7,[9][10][11]. MJD is one of the CAG repeat/polyglutamine disorders, which includes Huntington disease (HD), spinal and bulbar muscular atrophy, dentatorubropallidoluysian atrophy (DRPLA), and other spinocerebellar ataxias, such as SCA1, 2, 6, 7, 12, and 17 [19,20], while inhibition of the proteasome pathway enhances cell death [21,22].…”

Section: Cihr Author Manuscriptmentioning

confidence: 99%

“…5). These species could either represent different splice variants of the mouse Mjd gene (potentially corresponding to human H2 cDNA variant described by Ichikawa and colleagues [7]) or be the result of proteolysis. Their conservation in mouse and human suggests that they could be of functional relevance.…”

Section: Mouse Ataxin-3 Expression In Adult Mousementioning

confidence: 99%

“…All protein sequences were taken from the TrEMBL database. The accession numbers of human variants ataxin-3-v1, ataxin-3-v2/v3 as denoted in [28], and ataxin-3-v4 corresponding to H2 in [7]; rat ataxin-3;and mouse ataxin-3 are Q96TC4, Q96TC3, Q96TC3, BAB18798, O35815, and Q9CVD2, respectively. Multiple sequence alignment was constructed by means of CLUSTAL W [42].…”

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Genomic structure, promoter activity, and developmental expression of the mouse homologue of the Machado–Joseph disease (MJD) gene☆

et al. 2004

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Machado-Joseph disease (MJD) is a neurodegenerative disorder, caused by the expansion of the (CAG) n tract in the MJD gene. This encodes the protein ataxin-3, of unknown function. The mouse Mjd gene has a structure similar to that of its human counterpart and it also contains a TATA-less promoter. Its 5′ flanking region contains conserved putative binding regions for transcription factors Sp1, USF, Arnt, Max, E47, and MyoD. Upon differentiation of P19 cells, the Mjd gene promoter is preferentially activated in endodermal and mesodermal derivatives, including cardiac and skeletal myocytes; and less so in neuronal precursors. Mouse ataxin-3 is ubiquitously expressed during embryonic development and in the adult, with strong expression in regions of the CNS affected in MJD. It is particularly abundant in all types of muscle and in ciliated epithelial cells, suggesting that it may be associated with the cytoskeleton and may have an important function in cell structure and/or motility. KeywordsAtaxin-3; Polyglutamine; Spinocerebellar ataxia; Triplet repeat; Muscle; Myocytes; MyoD; E47; Max; Arnt Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is a neurodegenerative disorder of late onset and the most common dominant spinocerebellar ataxia worldwide (30% among all forms) [1]. Patients present with cerebellar ataxia and ☆ Supplementary data for this article may be found on ScienceDirect. CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptprogressive external ophthalmoplegia, associated in a variable degree with pyramidal signs, extrapyramidal signs (dystonia or rigidity), amyotrophy, and peripheral neuropathy [2]. Pathologically, MJD is characterized by neuronal loss in the spinocerebellar, dentate, pontine, and vestibular nuclei, the substantia nigra, the locus coeruleus, the palidoluysian complex, the motor cranial nerve and medulla anterior horn nuclei, and the dorsal root ganglia [2][3][4].The MJD causative gene was mapped to chromosome 14q32.1 in 1993 [5] and cloned in 1994 [6], but its structure has only recently been elucidated [7]. Alternative splicing of MJD results in the production of different isoforms of ataxin-3 [8], which are expressed in various tissues and have been detected both in the nucleus and in the cytoplasm [7,[9][10][11]. MJD is one of the CAG repeat/polyglutamine disorders, which includes Huntington disease (HD), spinal and bulbar muscular atrophy, dentatorubropallidoluysian atrophy (DRPLA), and other spinocerebellar ataxias, such as SCA1, 2, 6, 7, 12, and 17 [19,20], while inhibition of the proteasome pathway enhances cell death [21,22]. Another hypothesis for the mechanism of neurodegeneration is the possibility of amyloid formation, as in Alzheimer disease and other neurodegenerative disorders, but with a different subcellular location [23]. Infrared spectroscopy measurements have shown that ataxin-3, containing an expanded poly(Q) tract, also forms fibrils in vitro presenting a higher content of β sheets [24]. There is evidence ...

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“…both the number and the sizes of exons and introns-11 exons and 10 introns-are identical [7]. The Mjd gene contains a CAG repeat localized in exon 10, as occurs in the human gene.…”

Section: Discussionmentioning

confidence: 99%

Section: Cihr Author Manuscriptmentioning

confidence: 99%

Section: Cihr Author Manuscriptmentioning

confidence: 99%

Section: Mouse Ataxin-3 Expression In Adult Mousementioning

confidence: 99%

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Genomic structure, promoter activity, and developmental expression of the mouse homologue of the Machado–Joseph disease (MJD) gene☆

et al. 2004

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The <emph type="ital">APOE</emph> ε2 Allele Increases the Risk of Earlier Age at Onset in Machado-Joseph Disease

Bettencourt

Raposo²,

Kazachkova³

et al. 2011

Arch Neurol

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Background. Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder of late onset, caused by a (CAG) n expansion at the ATXN3 gene (14q32.1). Variation in age-at-onset is partially explained by the size of the (CAG) n tract in expanded alleles. The remaining variation should be the product of other factors, namely modifier genes. The genotype at the APOE locus has been described as a possible modifier in different neurological disorders, namely Parkinson (PD) and Huntington disease (HD). In the CNS, apolipoprotein E constitutes an important mediator of cholesterol transport/metabolism, which is essential for synaptic integrity and neuronal function.Objective. To investigate a modulating effect of the APOE polymorphism on ageat-onset of MJD. Design and Subjects.The APOE polymorphism was typed in a series of 192 MJD patients. Results.Cases with the ε2/ε3 genotype presented an earlier onset, when compared with those with ε3/ε3 or ε3/ε4. In this series of patients, the presence of an APOE ε2 allele implies a decrease of nearly 5 years in the age-at-onset. When combining, in a general linear model, several other predictors, namely the presence/absence of the APOE ε2 allele, with the size of the (CAG) n in expanded alleles, the model was significantly improved and the explanation of onset variance was raised from 59.8% to 66.5%. Furthermore, the presence of the ε2 allele was associated with an onset below 39 years (OR=5.00; 95% CI: 1.18-21.14). Conclusions.These findings indicate that the polymorphism at the APOE gene plays a role as a genetic modifier of MJD phenotype.

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The seesaw between normal function and protein aggregation: How functional interactions may increase protein solubility

2021

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Protein aggregation has been studied for at least 3 decades, and many of the principles that regulate this event are relatively well understood. Here, however, we present a different perspective to explain why proteins aggregate: we argue that aggregation may occur as a side-effect of the lack of one or more natural partners that, under physiologic conditions, would act as chaperones. This would explain why the same surfaces that have evolved for functional purposes are also those that favour aggregation. In the course of reviewing this field, we substantiate our hypothesis with three paradigmatic examples that argue for the generality of our proposal. An obvious corollary of this hypothesis is, of course, that targeting the physiological partners of a protein could be the most direct and specific approach to designing anti-aggregation molecules. Our analysis may thus inform a different strategy for combating diseases of protein aggregation and misfolding.

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The genomic structure and expression of MJD, the Machado-Joseph disease gene

Cited by 68 publications

References 31 publications

Genomic structure, promoter activity, and developmental expression of the mouse homologue of the Machado–Joseph disease (MJD) gene☆

Genomic structure, promoter activity, and developmental expression of the mouse homologue of the Machado–Joseph disease (MJD) gene☆

The <emph type="ital">APOE</emph> ε2 Allele Increases the Risk of Earlier Age at Onset in Machado-Joseph Disease

The seesaw between normal function and protein aggregation: How functional interactions may increase protein solubility

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