Machado–Joseph Disease Gene Product Identified in Lymphocytes and Brain

Wang, Guanghui; Ide, Kaori; Nukina, Nobuyuki; Goto, Jun; Ichikawa, Yaeko; Uchida, Kazuyo; Sakamoto, Terumi; Kanazawa, Ichiro

doi:10.1006/bbrc.1997.6484

Cited by 37 publications

(19 citation statements)

References 19 publications

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“…Mutant ataxin-3 expression throughout the brains of MJD patients is similar (Trottier et al, 1995Nishiyama et al, 1996;Paulson et al, 1997a;Schmitt et al, 1997;Wang et al, 1997). Thus, the increased concentration of the mutant ataxin-3 putative-cleavage fragment in selective brain regions is unlikely to result from a higher level of mutant ataxin-3 expression.…”

Section: Mutant Ataxin-3 Putative-cleavage Fragmentmentioning

confidence: 94%

A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical Concentration

Goti¹,

Katzen²,

Mez³

et al. 2004

J. Neurosci.

181

244

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Machado-Joseph disease (MJD) is an inherited neurodegenerative disorder caused by ataxin-3 with a polyglutamine expansion. It isproposed that a toxic cleavage fragment of mutant ataxin-3 alternatively spliced isoform mjd1a triggers neurodegeneration, although this fragment has not yet been detected in the brains of MJD patients or in animal models. We have now generated transgenic mice expressing human mutant (Q71) or normal (Q20) ataxin-3 mjd1a under the control of the mouse prion promoter. Q71 transgenic mice expressing mutant ataxin-3 mjd1a above a critical level developed a phenotype similar to MJD including progressive postural instability, gait and limb ataxia, weight loss, premature death, neuronal intranuclear inclusions, and decreased tyrosine hydroxylase-positive neurons in the substantia nigra (determined by unbiased stereology). Q20 transgenic mice had normal behavior and pathology. Brains from sick Q71 transgenic mice contained an abundant mutant ataxin-3 mjd1a putative-cleavage fragment (Fragment), which was scarce in normal Q71 transgenic mice. Reactivity of the Fragment with a panel of antibodies and comigration with truncations of mutant ataxin-3 revealed that it contained residues C terminal to amino acid 221 to include the polyglutamine expansion. A similar portion of mutant ataxin-3 mjd1a expressed in transfected neuroblastoma cells was toxic above a critical concentration. The Fragment was more abundant in two affected brain regions of MJD patients. Thus, we have developed a murine model for mutant ataxin-3 mjd1a toxicity and identified a putativecleavage fragment of the disease protein in the brains of these transgenic mice and MJD patients that is cytotoxic above a critical concentration.

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Section: Mutant Ataxin-3 Putative-cleavage Fragmentmentioning

confidence: 94%

A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical Concentration

Goti¹,

Katzen²,

Mez³

et al. 2004

J. Neurosci.

181

244

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“…Besides HD, other such diseases include the spinocerebellular ataxias (spinocerebellular ataxias 1, 2, 3 (MJD), and 7), caused by expan-sions in the respective ataxin gene, spinocerebellular ataxia 6 (CACNL1A4), spinal bulbar muscular atrophy/Kennedy's disease (AR), and DRPLA (atrophin-1) (14). With the exception of ataxin-3, for which polymorphic C termini adjacent to the polyglutamine repeat have been reported (52), each protein sequence contains proline-rich regions adjacent to the polyglutamine repeats that are expanded in the disease states. Within the proline-rich domains, these proteins contain a minimum of one consensus PXXP motif as well, although the majority contain several.…”

Section: Waf1/cip1mentioning

confidence: 99%

The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription

Steffan

Kazantsev

Spasić-Bošković

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

962

649

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Huntington's Disease (HD) is caused by an expansion of a polyglutamine tract within the huntingtin (htt) protein. Pathogenesis in HD appears to include the cytoplasmic cleavage of htt and release of an amino-terminal fragment capable of nuclear localization. We have investigated potential consequences to nuclear function of a pathogenic amino-terminal region of htt (httex1p) including aggregation, protein-protein interactions, and transcription. httex1p was found to coaggregate with p53 in inclusions generated in cell culture and to interact with p53 in vitro and in cell culture. Expanded httex1p represses transcription of the p53-regulated promoters, p21 WAF1/CIP1 and MDR-1. httex1p was also found to interact in vitro with CREB-binding protein (CBP) and mSin3a, and CBP to localize to neuronal intranuclear inclusions in a transgenic mouse model of HD. These results raise the possibility that expanded repeat htt causes aberrant transcriptional regulation through its interaction with cellular transcription factors which may result in neuronal dysfunction and cell death in HD.

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“…Comparison of the nucleotide and translated amino acid sequences with the existing data bases at BLAST, GenBank TM , and PIR revealed that sertolin shared about a 20% homology at the amino acid level in a short stretch of sequence (amino acid residues 88 -121) with the rat spinocerebellar ataxia type 3 antaxin protein (amino acid residues 30 -63) (52,53) 4 and its human homolog, the Machado-Joseph disease josephin protein (amino acid residues 29 -62) (54 -57), a predominantly cytoplasmic protein that is widely distributed in human neurons but also detected in the nuclei of neurons and glial cells (58,59). Machado-Joseph disease, in addition to Huntington's disease (60), are two of several neurodegenerative diseases where expanded CAG repeats are found to associate with these disorders that translate into polyglutamine stretches (61)(62)(63).…”

Section: Discussionmentioning

confidence: 99%

Sertolin Is a Novel Gene Marker of Cell-Cell Interactions in the Rat Testis

Mruk¹,

Cheng²

1999

Journal of Biological Chemistry

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A novel testicular protein designated sertolin was cloned. The full-length sertolin cDNA consists of 853 base pairs with an open reading frame of 381 base pairs coding for a 127-amino acid polypeptide that shares limited identities with antaxin/josephin and thrombospondin proteins. Sertolin (calculated molecular mass, 13,759 daltons) has two mRNA transcripts of 2.3 and 1 kilobase. A 22-amino acid peptide based on the deduced amino acid sequence of sertolin (NH 2 -KKEHFNLFKAASVSHLVQV-VPQ) was synthesized and used for polyclonal antibody production. Immunoblot analysis detected a 17-kDa immunoreactive band in the Sertoli cell cytosol. Using Sertoli-germ cell cocultures, sertolin expression was found to be reduced by as much as 5-fold at the time when germ cells attach onto Sertoli cells but preceding the establishment of specialized inter-Sertoli-germ cell junctions. Neither FSH nor 17␤-hydroxy-5␣-androstan-3-one was able to affect sertolin expression, whereas estradiol-17␤ and progesterone induced a significant increase in Sertoli cell sertolin expression in vitro. In addition, interleukin-1␣, a germ cell-derived cytokine, was also able to elicit a transient but significant increase in Sertoli cell sertolin expression. Sertolin expression was also shown to increase with testicular development and is likely to be associated with the onset of spermatogenesis. In addition, sertolin expression increased in the testis when generalized inflammation was induced in adult rats by injection of fermented yeast. These results show that sertolin will be useful in characterizing cell-cell interactions in the testis.Apart from the numerous morphological and molecular changes that take place in developing germ cells during spermatogenesis, these cells also migrate from the basal to the adluminal compartment, where fully developed spermatids are released into the tubular lumen at spermiation (1, 2). During the process of germ cell movement, it is envisioned that specialized inter-Sertoli and Sertoli-germ cell junctions must be intermittently disassembled and reassembled in a highly organized manner. As such, germ cell movement must consist of intermittent phases of junction disassembly and reassembly. These events probably also require the active participation of several proteases, protease inhibitors, junctional complex components, and signaling molecules that are found in the testis (3, 4). However, the intricate cascade(s) of events underlying spermatogenesis with respect to germ cell migration has not been elucidated. Recent studies from this laboratory have demonstrated that when germ cells consisting largely of spermatogonia and spermatocytes are cocultured with Sertoli cells in vitro for a short period of time prior to the establishment of specialized intercellular junctions, there are changes in the expression of several proteases, protease inhibitors (5, 6), and cell adhesion molecules (7) showing that germ cell attachment to Sertoli cells with the eventual establishment of specialized cell junctions consists of a series...

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Machado–Joseph Disease Gene Product Identified in Lymphocytes and Brain

Cited by 37 publications

References 19 publications

A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical Concentration

A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical Concentration

The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription

Sertolin Is a Novel Gene Marker of Cell-Cell Interactions in the Rat Testis

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