共查询到20条相似文献,搜索用时 15 毫秒
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Kubodera T Yokota T Ohwada K Ishikawa K Miura H Matsuoka T Mizusawa H 《Neuroscience letters》2003,341(1):74-78
Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease caused by small CAG repeat expansion in the alpha1A calcium channel gene. We found that the human alpha1A calcium channel protein expressed in human embryonic kidney 293T cells produces a 75 kDa C-terminal fragment. This fragment is more toxic to cells than the full-length alpha1A calcium channel, regardless of polyglutamine tract length. In cells stably transfected with plasmids of full-length alpha1A calcium channel cDNAs, the C-terminal fragment protein is present in the mutant transformant but not in the wild-type one, indicative that this C-terminal fragment with the expanded polyglutamine tract is more resistant to proteolysis than that with the normal sized polyglutamine tract. We speculate that the toxic C-terminal fragment, in which resistance to proteolysis is rendered by the expanded polyglutamine, has a key role in the pathological mechanism of SCA6. 相似文献
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Simeoni S Mancini MA Stenoien DL Marcelli M Weigel NL Zanisi M Martini L Poletti A 《Human molecular genetics》2000,9(1):133-144
Spinal and bulbar muscular atrophy (SBMA) is associated with an abnormal expansion of the (CAG)(n)repeat in the androgen receptor (AR) gene. Similar mutations have been reported in other proteins that cause neurodegenerative disorders. The CAG-coded elongated polyglutamine (polyGln) tracts induce the formation of neuronal intracellular aggregates. We have produced a model to study the effects of potentially 'neurotoxic' aggregates in SBMA using immortalized motoneuronal cells (NSC34) transfected with AR containing polyGln repeats of different sizes [(AR.Q(n = 0, 23 or 46)]. Using chimeras of AR.Q(n) and the green fluorescent protein (GFP), we have shown that aggregate formation occurs when the polyGln tract is elongated and AR is activated by androgens. In NSC34 cells co-expressing the AR with the polyGln of pathological length (AR.Q46) and the GFP we have noted the presence of several dystrophic neurites. Cell viability analyses have shown a reduced growth/survival rate in NSC34 expressing the AR.Q46, whereas testosterone treatment partially counteracted both cell death and the formation of dystrophic neurites. These observations indicate the lack of correlation between aggregate formation and cell survival, and suggest that neuronal degeneration in SBMA might be secondary to axonal/dendritic insults. 相似文献
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Thomas PS Fraley GS Damian V Damien V Woodke LB Zapata F Sopher BL Plymate SR La Spada AR 《Human molecular genetics》2006,15(14):2225-2238
X-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a polyglutamine (polyQ) disease in which the affected males suffer progressive motor neuron degeneration accompanied by signs of androgen insensitivity, such as gynecomastia and reduced fertility. SBMA is caused by CAG repeat expansions in the androgen receptor (AR) gene resulting in the production of AR protein with an extended glutamine tract. SBMA is one of nine polyQ diseases in which polyQ expansion is believed to impart a toxic gain-of-function effect upon the mutant protein, and initiate a cascade of events that culminate in neurodegeneration. However, whether loss of a disease protein's normal function concomitantly contributes to the neurodegeneration remains unanswered. To address this, we examined the role of normal AR function in SBMA by crossing a highly representative AR YAC transgenic mouse model with 100 glutamines (AR100) and a corresponding control (AR20) onto an AR null (testicular feminization; Tfm) background. Absence of endogenous AR protein in AR100Tfm mice had profound effects upon neuromuscular and endocrine-reproductive features of this SBMA mouse model, as AR100Tfm mice displayed accelerated neurodegeneration and severe androgen insensitivity in comparison to AR100 littermates. Reduction in size and number of androgen-sensitive motor neurons in the spinal cord of AR100Tfm mice underscored the importance of AR action for neuronal health and survival. Promoter-reporter assays confirmed that AR transactivation competence diminishes in a polyQ length-dependent fashion. Our studies indicate that SBMA disease pathogenesis, both in the nervous system and the periphery, involves two simultaneous pathways: gain-of-function misfolded protein toxicity and loss of normal protein function. 相似文献
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Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture 总被引:11,自引:12,他引:11
Cooper JK; Schilling G; Peters MF; Herring WJ; Sharp AH; Kaminsky Z; Masone J; Khan FA; Delanoy M; Borchelt DR; Dawson VL; Dawson TM; Ross CA 《Human molecular genetics》1998,7(5):783-790
Huntington's disease (HD) is a progressive neurodegenerative disorder
caused by an expanding CAG repeat coding for polyglutamine in the
huntingtin protein. Recent data have suggested the possibility that an
N-terminal fragment of huntingtin may aggregate in neurons of patients with
HD, both in the cytoplasm, forming dystrophic neurites, and in the nucleus,
forming intranuclear neuronal inclusion bodies. An animal model of HD using
the short N-terminal fragment of huntingtin has also been found to have
intranuclear inclusions and this same fragment can aggregate in vitro . We
have now developed a cell culture model demonstrating that N-terminal
fragments of huntingtin with expanded glutamine repeats aggregate both in
the cytoplasm and in the nucleus. Neuroblastoma cells transiently
transfected with full-length huntingtin constructs with either a normal or
expanded repeat had diffuse cytoplasmic localization of the protein. In
contrast, cells transfected with truncated N-terminal fragments showed
aggregation only if the glutamine repeat was expanded. The aggregates were
often ubiquitinated. The shorter truncated product appeared to form more
aggregates in the nucleus. Cells transfected with the expanded repeat
construct but not the normal repeat construct showed enhanced toxicity to
the apoptosis- inducing agent staurosporine. These data indicate that
N-terminal truncated fragments of huntingtin with expanded glutamine
repeats can aggregate in cells in culture and that this aggregation can be
toxic to cells. This model will be useful for future experiments to test
mechanisms of aggregation and toxicity and potentially for testing
experimental therapeutic interventions.
相似文献
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Spinal and bulbar muscular atrophy: ligand-dependent pathogenesis and therapeutic perspectives 总被引:2,自引:0,他引:2
Katsuno M Adachi H Tanaka F Sobue G 《Journal of molecular medicine (Berlin, Germany)》2004,82(5):298-307
Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. SBMA exclusively affects males, while females are usually asymptomatic. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine (polyQ) tract in the first exon of the androgen receptor (AR) gene. The histopathological hallmark is the presence of nuclear inclusions containing mutant truncated ARs with expanded polyQ tracts in the residual motor neurons in the brainstem and spinal cord, as well as in some other visceral organs. The AR ligand, testosterone, accelerates AR dissociation from heat shock proteins and thus its nuclear translocation. Ligand-dependent nuclear accumulation of mutant ARs has been implicated in the pathogenesis of SBMA. Transgenic mice carrying the full-length human AR gene with an expanded polyQ tract demonstrate neuromuscular phenotypes, which are profound in males. Their SBMA-like phenotypes are rescued by castration, and aggravated by testosterone administration. Leuprorelin, an LHRH agonist that reduces testosterone release from the testis, inhibits nuclear accumulation of mutant ARs, resulting in the rescue of motor dysfunction in the male transgenic mice. However, flutamide, an androgen antagonist promoting nuclear translocation of the AR, yielded no therapeutic effect. The degradation and cleavage of the AR protein are also influenced by the ligand, contributing to the pathogenesis. Testosterone thus appears to be the key molecule in the pathogenesis of SBMA, as well as main therapeutic target of this disease. 相似文献
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McManamny P Chy HS Finkelstein DI Craythorn RG Crack PJ Kola I Cheema SS Horne MK Wreford NG O'Bryan MK De Kretser DM Morrison JR 《Human molecular genetics》2002,11(18):2103-2111
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease, caused by the expansion of a trinucleotide repeat (TNR) in exon 1 of the androgen receptor (AR) gene. This disorder is characterized by degeneration of motor and sensory neurons, proximal muscular atrophy, and endocrine abnormalities, such as gynecomastia and reduced fertility. We describe the development of a transgenic model of SBMA expressing a full-length human AR (hAR) cDNA carrying 65 (AR(65)) or 120 CAG repeats (AR(120)), with widespread expression driven by the cytomegalovirus promoter. Mice carrying the AR(120) transgene displayed behavioral and motor dysfunction, while mice carrying 65 CAG repeats showed a mild phenotype. Progressive muscle weakness and atrophy was observed in AR(120) mice and was associated with the loss of alpha-motor neurons in the spinal cord. There was no evidence of neurodegeneration in other brain structures. Motor dysfunction was observed in both male and female animals, showing that in SBMA the polyglutamine repeat expansion causes a dominant gain-of-function mutation in the AR. The male mice displayed a progressive reduction in sperm production consistent with testis defects reported in human patients. These mice represent the first model to reproduce the key features of SBMA, making them a useful resource for characterizing disease progression, and for testing therapeutic strategies for both polyglutamine and motor neuron diseases. 相似文献
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K Ishikawa H Fujigasaki H Saegusa K Ohwada T Fujita H Iwamoto Y Komatsuzaki S Toru H Toriyama M Watanabe N Ohkoshi S Shoji I Kanazawa T Tanabe H Mizusawa 《Human molecular genetics》1999,8(7):1185-1193
Spinocerebellar ataxia type 6 (SCA6) is one of the eight neurodegenerative diseases caused by a tri-nucleotide (CAG) repeat expansion coding polyglutamine (CAG repeat/polyglutamine diseases) and is characterized by late onset autosomal dominant cerebellar ataxia and predominant loss of cerebellar Purkinje cells. Although the causative, small and stable CAG repeat expansion for this disease has been identified in the [alpha]1A voltage-dependent calcium channel gene (CACNA1A), the mechanism which leads to predominant Purkinje cell degeneration is totally unknown. In this study, we show that the calcium channel mRNA/protein containing the CAG repeat/polyglutamine tract is most intensely expressed in Purkinje cells of human brains. In SCA6 brains, numerous oval or rod-shaped aggregates were seen exclusively in the cytoplasm of Purkinje cells. These cytoplasmic inclusions were not ubiquitinated, which contrasts with the neuronal intra-nuclear inclusions of other CAG repeat/polyglutamine diseases. In cultured cells, formation of perinuclear aggregates of the channel protein and apoptotic cell death were seen when transfected with full-length CACNA1A coding an expanded polyglutamine tract. The present study indicates that the mechanism of neurodegeneration in SCA6 is associated with cytoplasmic aggregations of the [alpha]1A calcium channel protein caused by a small CAG repeat/polyglutamine expansion in CACNA1A. 相似文献
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Xiao H Yu Z Wu Y Nan J Merry DE Sekiguchi JM Ferguson DO Lieberman AP Dressler GR 《Human molecular genetics》2012,21(19):4225-4236
Glutamine (Q) expansion diseases are a family of degenerative disorders caused by the lengthening of CAG triplet repeats present in the coding sequences of seemingly unrelated genes whose mutant proteins drive pathogenesis. Despite all the molecular evidence for the genetic basis of these diseases, how mutant poly-Q proteins promote cell death and drive pathogenesis remains controversial. In this report, we show a specific interaction between the mutant androgen receptor (AR), a protein associated with spinal and bulbar muscular atrophy (SBMA), and the nuclear protein PTIP (Pax Transactivation-domain Interacting Protein), a protein with an unusually long Q-rich domain that functions in DNA repair. Upon exposure to ionizing radiation, PTIP localizes to nuclear foci that are sites of DNA damage and repair. However, the expression of poly-Q AR sequesters PTIP away from radiation-induced nuclear foci. This results in sensitivity to DNA-damaging agents and chromosomal instabilities. In a mouse model of SBMA, evidence for DNA damage is detected in muscle cell nuclei and muscular atrophy is accelerated when one copy of the gene encoding PTIP is removed. These data provide a new paradigm for understanding the mechanisms of cellular degeneration observed in poly-Q expansion diseases. 相似文献
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Spinocerebellar ataxia type-1 and spinobulbar muscular atrophy gene products interact with glyceraldehyde-3-phosphate dehydrogenase 总被引:4,自引:2,他引:4
Koshy B; Matilla T; Burright EN; Merry DE; Fischbeck KH; Orr HT; Zoghbi HY 《Human molecular genetics》1996,5(9):1311-1318
Spinocerebellar ataxia type1 (SCA1) is one of several neurodegenerative
disorders caused by expansions of translated CAG trinucleotide repeats
which code for polyglutamine in the respective proteins. Most hypotheses
about the molecular defect in these disorders suggest a gain of function,
which may involve interactions with other proteins via the expanded
polyglutamine tract. In this study we used ataxin-1, the SCA1 gene product,
as a bait in the yeast two-hybrid system and identified the glycolytic
enzyme glyceraldehyde-3-phosphate dehydrogenase as an ataxin-1 interacting
protein. In addition, the yeast two hybrid data demonstrate that wild type
and mutant ataxin-1 form homo and heterodimers. Physical interaction
between GAPDH and ataxin-1 was also demonstrated in vitro. To investigate
if GAPDH might interact with other glutamine repeat-containing proteins
involved in neurodegenerative disorders, we tested its binding to the
androgen receptor which is mutated in spinobulbar muscular atrophy. The
androgen receptor interacts with GAPDH both in the yeast two-hybrid system
and in vitro. The binding of both ataxin-1 and the androgen receptor to
GAPDH does not vary with the length of the polyglutamine tract. While
provocative, these findings do not address the selective neuronal loss in
each of these disorders in light of the wide expression patterns of GAPDH
and the respective polyglutamine containing proteins. Nonetheless, such
interactions may increase the susceptibility of specific neurons to a
variety of insults and initiate degeneration.
相似文献
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Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy 总被引:3,自引:17,他引:3
Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease
caused by the expansion of a polyglutamine repeat within the androgen
receptor (AR). We have studied the mutant AR in an in vitro system, and
find both aggregation and proteolytic processing of the AR protein to occur
in a polyglutamine repeat length-dependent manner. In addition, we find the
aberrant metabolism of expanded repeat AR to be coupled to cellular
toxicity, indicating a likely molecular basis for the toxic gain of AR
function that produces neuronal degeneration in SBMA.
相似文献
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Dadze S Wieland C Jakubiczka S Funke K Schröder E Royer-Pokora B Willers R Wieacker PF 《Molecular human reproduction》2000,6(3):207-214
The androgen receptor (AR) gene, located on the X-chromosome at Xq11-12, contains in exon 1 a polymorphic CAG repeat which codes for a polyglutamine tract. Contractions of the CAG repeat are said to be related to prostate cancer. In contrast, sizeable expansion of the CAG repeat can cause spinal and bulbar muscular atrophy (SBMA). In infertile patients of Chinese origin and in a Melbourne multinational population impaired sperm production has been postulated to be related to moderate expansions of the polyglutamine tract. In a study of a Swedish population of infertile patients these findings could not be corroborated. The aim of our investigation was to examine the correlation between the length of the CAG repeat and impaired sperm production in an infertile Caucasoid patient sample of German ethnic origin. We found no statistically significant relationship between the size of the CAG repeat or polyglutamine tract and idiopathic impaired sperm production in the population studied. The variability of the results by various investigators may be attributed to different ethnic origins and hence different genetic modifiers of the populations studied and/or to the high probability that these infertile males may represent a heterogeneous group with respect to the causes of defective spermatogenesis. 相似文献
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Transglutaminase potentiates ligand-dependent proteasome dysfunction induced by polyglutamine-expanded androgen receptor 总被引:2,自引:0,他引:2
Mandrusiak LM Beitel LK Wang X Scanlon TC Chevalier-Larsen E Merry DE Trifiro MA 《Human molecular genetics》2003,12(13):1497-1506
Expansion of the CAG trinucleotide repeat encoding glutamine in the androgen receptor gene leads to spinobulbar muscular atrophy (SBMA), a neurodegenerative disorder in a family of polyglutamine diseases with enigmatic pathogenic mechanisms. One established property of glutamine residues is their ability to act as an amine accepter in a transglutaminase-catalyzed reaction, resulting in a proteolytically resistant glutamyl-lysine cross-link. To examine underlying disease mechanisms we investigated the relationship between polyglutamine-expanded androgen receptor and transglutaminase. We found androgen receptor N-terminal fragments are a substrate for transglutaminase. Western blots of the proteins following incubation with transglutaminase show that several different epitopes of the AR appear to be lost. We propose that this is due to the transglutaminase cross-linking of the AR, which interferes with antibody recognition. Furthermore, HEK GFP(u)-1 cells expressing polyglutamine-expanded androgen receptor and transglutaminase exhibit ligand-dependent proteasome dysfunction; this effect was not observed in the presence of cystamine, a transglutaminase inhibitor. In addition, transglutaminase-mediated isopeptide bonds were detected in brains of SBMA transgenic mice, but not in controls, suggesting involvement of transglutaminase-catalyzed reactions in polyglutamine disease pathogenesis. Our hypothesis is that cross-linked AR cannot to be degraded by the proteasome and obstructs the proteasome pore, preventing normal function. Because of the central role the ubiquitin-proteasome degradation system plays in fundamental cellular processes, any alteration in its function could cause cell death, ultimately contributing to SBMA pathogenesis. 相似文献
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V Biancalana F Serville J Pommier J Julien A Hanauer J L Mandel 《Human molecular genetics》1992,1(4):255-258
Increased length of a protein-coding CAG repeat within the androgen receptor gene appears to be the only type of mutation responsible for spino-bulbal muscular atrophy (SBMA or Kennedy disease). We have analysed a large 4-generation SBMA family and found that the mutant allele was unstable upon transmission from parent to child, with a documented variation from 46 to 53 repeats and a tendency to increase in size (7 increases and a single decrease in 17 events), which appeared stronger upon transmission from a male than from a female. Our results suggest also limited somatic instability of the abnormal allele, with observable variation of up to 2-3 repeats. This indicates that the behavior of the CAG repeat is similar to that observed for small premutations in the fragile X syndrome, or small abnormal alleles in myotonic dystrophy, two diseases which are caused by expansion of an unstable trinucleotide repeat. 相似文献