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Patricia Maciel - One of the best experts on this subject based on the ideXlab platform.
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segregation distortion of wild type alleles at the Machado Joseph Disease locus a study in normal families from the azores islands portugal
Journal of Human Genetics, 2008Co-Authors: Conceicao Bettencourt, Patricia Maciel, Rafael Montiel, Raquel Nunes Fialho, Cristina Santos, Jacome Brugesarmas, Manuela LimaAbstract:Machado-Joseph Disease (MJD) is caused by an expansion of a triplet repeat with a CAG motif at the ATXN3 gene. The putative segregation ratio distortion (SRD) of alleles can play an important role in the non-Mendelian behaviour of triplet repeat loci. To study the stability and infer the segregation patterns of wild-type MJD alleles, the size of the (CAG)(n) tract was analysed in 102 normal sibships, representing 428 meioses. No mutational events were detected during the transmission of alleles. Segregation analysis showed that the smaller alleles were preferentially transmitted (56.9%). Considering maternal meioses alone, such preference was still detected (55.7%) but without statistical significance. A positive correlation was observed for the difference in length between the two alleles constituting the transmitters' genotype (D) and the frequency of transmission of the smaller alleles. The results suggest that small D values are not enough to modify the probability of allele transmission. When transmissions involving genotypes with D
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functional genomics and biochemical characterization of the c elegans orthologue of the Machado Joseph Disease protein ataxin 3
The FASEB Journal, 2007Co-Authors: Ana Joao Rodrigues, Jorge Sequeiros, Maria Do Carmo Costa, Giovanni Coppola, Claudia Teixeira Dos A Santos, Michael Ailion, Daniel H Geschwind, Patricia MacielAbstract:Machado-Joseph Disease (MJD) is the most common dominant spinocerebellar ataxia. MJD is caused by a CAG trinucleotide expansion in the ATXN3 gene, which encodes a protein named ataxin-3. Ataxin-3 has been proposed to act as a deubiquitinating enzyme in the ubiquitin-proteasome pathway and to be involved in transcriptional repression; nevertheless, its precise biological function(s) remains unknown. To gain further insight into the function of ataxin-3, we have identified the Caenorhabditis elegans orthologue of the ATXN3 gene and characterized its pattern of expression, developmental regulation, and subcellular localization. We demonstrate that, analogous to its human orthologue, C. elegans ataxin-3 has deubiquitinating activity in vitro against polyubiquitin chains with four or more ubiquitins, the minimum ubiquitin length for proteasomal targeting. To further evaluate C. elegans ataxin-3, we characterized the first known knockout animal models both phenotypically and biochemically, and found that the tw...
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somatic mosaicism in the central nervous system in spinocerebellar ataxia type 1 and Machado Joseph Disease
Annals of Neurology, 1996Co-Authors: I Lopescendes, Isabel Silveira, Claudia Gaspar, Patricia Maciel, Stephen J Kish, Yves Robitaille, Brent H ClarkAbstract:Spinocerebellar ataxia type 1 and Machado-Joseph Disease are two autosomal dominant cerebellar ataxias caused by expansions of unstable GAG repeats in the coding region of the causative genes. The selectivity of cell death and the resulting characteristic neuropathological features in each of these Diseases are not explained by the gene expression patterns. Since the repeat size correlates with age at onset and severity of these Diseases, somatic mosaicism, the result of mitotic instability of the GAG repeat, could be the basis for specificity of neurodegeneration ; brain structures with larger expanded repeats would be more severely affected. To study the association between neuropathological changes and somatic mosaicism of the GAG repeat size in the central nervous system of patients with these two ataxias, we determined the size of the (CAG)n expansion in 20 different regions of the brain, brainstem, cerebellum, and spinal cord from 3 patients with spinocerebellar ataxia type 1 and 3 with Machado-Joseph Disease ; these regions were selected for their differential neuropathological involvement in the two disorders. We observed a considerable homogeneity of repeat size ranges in all but 1 of the 20 regions examined : The cerebellar cortex showed slightly smaller (GAG)n tracts in all specimens from both groups of patients. Out results suggest that the pattern of repeat size mosaicism, similar in spinocerebellar ataxia type 1 and Machado-Joseph Disease, reflects the developmental pathways and cell composition of different central nervous system regions and is not the cause of selective cell death in these disorders.
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frequency of spinocerebellar ataxia type 1 dentatorubropallidoluysian atrophy and Machado Joseph Disease mutations in a large group of spinocerebellar ataxia patients
Web Science, 1996Co-Authors: Isabel Silveira, Claudia Gaspar, Paula Coutinho, Patricia Maciel, Stephen J Kish, Mi Botez, Iscia Lopescendes, Helio Ghizoni TeiveAbstract:The spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders varying in both clinical manifestations and mode of inheritance. Six different genes causing autosomal dominant SCA are mapped: SCA1, SCA2, Machado-Joseph Disease (MJD)/SCA3, SCA4, SCA5, and dentatorubropallidoluysian atrophy (DRPLA). Expansions of an unstable trinucleotide CAG repeat cause three of these disorders: SCA type 1 (SCA1), MJD, and DRPLA. We determine the frequency of the SCA1, DRPLA, and MJD mutations in a large group of unrelated SCA patients with various patterns of inheritance and different ethnic backgrounds. We studied 92 unrelated SCA patients. The frequency of the SCA1 mutation was 3% in the overall patient group and 10% in the non-Portuguese dominantly inherited SCA subgroup. We found that DRPLA mutation in only one Japanese patient, who was previously diagnosed with this Disease. We identified the MJD mutation in 41% of the overall patient group, which included 38 autosomal dominant kindreds of Portuguese origin; the frequency of the MJD mutation among the non-Portuguese dominantly inherited cases was 17%. These results suggest that SCA may be occasionally caused by the SCA1 mutation and rarely caused by the DRPLA mutation and that, to date, the MJD mutation seems to be the most common cause of dominantly inherited SCA. Finally, our results suggest that recessively inherited cases of SCA are not caused by the known trinucleotide repeat expansions.
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correlation between cag repeat length and clinical features in Machado Joseph Disease
American Journal of Human Genetics, 1995Co-Authors: Isabel Silveira, Claudia Gaspar, Paula Coutinho, Patricia Maciel, Anita L Destefano, Joao Radvany, David M DawsonAbstract:Machado-Joseph Disease (MJD) is associated with the expansion of a CAG trinucleotide repeat in a novel gene on 14q32.1. We confirmed the presence of this expansion in 156 MJD patients from 33 families of different geographic origins: 15 Portuguese Azorean, 2 Brazilian, and 16 North American of Portuguese Azorean descent. Normal chromosomes contain between 12 and 37 CAG repeats in the MJD gene, whereas MJD gene carriers have alleles within the expanded range of 62-84 CAG units. The distribution of expanded alleles and the gap between normal and expanded allele sizes is either inconsistent with a premutation hypothesis or most (if not all) of the alleles we studied descend from a common ancestor. There is a strong correlation between the expanded repeat size and the age at onset of the Disease as well as the clinical presentation. There is mild instability of the CAG tract length with transmission of the expanded alleles; both increase and decrease in size between parents and progeny occur, with larger variations in male than in female transmissions. Together, these effects can partly explain the variability of age at onset and of phenotypic features in MJD; however, other modifying factors must exist.
Luís Pereira De Almeida - One of the best experts on this subject based on the ideXlab platform.
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Re-establishing ataxin-2 downregulates translation of mutant ataxin-3 and alleviates Machado-Joseph Disease.
Brain : a journal of neurology, 2015Co-Authors: Clévio Nóbrega, Hirokazu Hirai, Sara Carmo-silva, David Albuquerque, Ana Vasconcelos-ferreira, Udaya-geetha Vijayakumar, Liliana Mendonça, Luís Pereira De AlmeidaAbstract:Machado-Joseph Disease is a progressive neurodegenerative disorder associated with the polyQ-expanded ataxin-3 (encoded by ATXN3), for which no therapy is available. With the aim of clarifying the mechanism of neurodegeneration, we hypothesized that the abnormally long polyQ tract would interact aberrantly with ataxin-2 (encoded by ATXN2), another polyQ protein whose function has recently been linked to translational regulation. Using patient's samples and cellular and animal's models we found that in Machado-Joseph Disease: (i) ataxin-2 levels are reduced; and (ii) its subcellular localization is changed towards the nucleus. Restoring ataxin-2 levels by lentiviral-mediated overexpression: (i) reduced mutant ataxin-3 levels; and (ii) rescued behaviour defects and neuropathology in a transgenic mouse model of Machado-Joseph Disease. Conversely (i) mutating the ataxin-2 motif that enables binding to its natural interactor and translation activator poly(A)-binding protein; or (ii) overexpressing poly(A)-binding protein, had opposite effects, increasing mutant ataxin-3 translation and aggregation. This work suggests that in Machado-Joseph Disease, mutant ataxin-3 drives an abnormal reduction of ataxin-2 levels, which overactivates poly(A)-binding protein, increases translation of mutant ataxin-3 and other proteins and aggravates Machado-Joseph Disease. Re-establishment of ataxin-2 levels reduces mutant ataxin-3 and alleviates Machado-Joseph Disease pathogenesis opening a new avenue for therapeutic intervention in this and potentially other polyQ disorders.
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calpain inhibition reduces ataxin 3 cleavage alleviating neuropathology and motor impairments in mouse models of Machado Joseph Disease
Human Molecular Genetics, 2014Co-Authors: Ana Teresa Simoes, Nélio Gonçalves, Rui Jorge Nobre, Carlos B Duarte, Luís Pereira De AlmeidaAbstract:Machado-Joseph Disease (MJD) is the most prevalent autosomal dominantly inherited cerebellar ataxia. It is caused by an expanded CAG repeat in the ATXN3 gene, which translates into a polyglutamine tract within the ataxin-3 protein. Present treatments are symptomatic and do not prevent Disease progression. As calpain overactivation has been shown to contribute to mutant ataxin-3 proteolysis, translocation to the nucleus, inclusions formation and neurodegeneration, we investigated the potential role of calpain inhibition as a therapeutic strategy to alleviate MJD pathology. For this purpose, we administered orally the calpain inhibitor BDA-410 to a lentiviral mouse model of MJD. Western-blot and immunohistochemical analysis revealed the presence of N- and C-terminal mutant ataxin-3 fragments and the colocalization of large inclusions with cleaved caspase-3 in the mice brain. Oral administration of the calpain inhibitor BDA-410 decreased both fragments formation and full-length ataxin-3 levels, reduced aggregation of mutant ataxin-3 and prevented cell injury and striatal and cerebellar degeneration. Importantly, in correlation with the preserved cerebellar morphology, BDA-410 prevented motor behavioural deficits. In conclusion, BDA-410 alleviates Machado-Joseph neuropathology and may therefore be an effective therapeutic option for MJD.
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silencing mutant ataxin 3 rescues motor deficits and neuropathology in Machado Joseph Disease transgenic mice
PLOS ONE, 2013Co-Authors: Clévio Nóbrega, Hirokazu Hirai, David Albuquerque, Isabel Onofre, Nicole Déglon, Isabel Nascimentoferreira, Luís Pereira De AlmeidaAbstract:Machado-Joseph Disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly-inherited neurodegenerative disorder caused by the over-repetition of a CAG codon in the MJD1 gene. This expansion translates into a polyglutamine tract that confers a toxic gain-of-function to the mutant protein – ataxin-3, leading to neurodegeneration in specific brain regions, with particular severity in the cerebellum. No treatment able to modify the Disease progression is available. However, gene silencing by RNA interference has shown promising results. Therefore, in this study we investigated whether lentiviral-mediated allele-specific silencing of the mutant ataxin-3 gene, after Disease onset, would rescue the motor behavior deficits and neuropathological features in a severely impaired transgenic mouse model of MJD. For this purpose, we injected lentiviral vectors encoding allele-specific silencing-sequences (shAtx3) into the cerebellum of Diseased transgenic mice expressing the targeted C-variant of mutant ataxin-3 present in 70% of MJD patients. This variation permits to discriminate between the wild-type and mutant forms, maintaining the normal function of the wild-type allele and silencing only the mutant form. Quantitative analysis of rotarod performance, footprint and activity patterns revealed significant and robust alleviation of gait, balance (average 3-fold increase of rotarod test time), locomotor and exploratory activity impairments in shAtx3-injected mice, as compared to control ones injected with shGFP. An important improvement of neuropathology was also observed, regarding the number of intranuclear inclusions, calbindin and DARPP-32 immunoreactivity, fluorojade B and Golgi staining and molecular and granular layers thickness. These data demonstrate for the first time the efficacy of gene silencing in blocking the MJD-associated motor-behavior and neuropathological abnormalities after the onset of the Disease, supporting the use of this strategy for therapy of MJD.
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calpastatin mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis nuclear localization and aggregation relieving Machado Joseph Disease
Brain, 2012Co-Authors: Ana T Simões, Nicole Déglon, Nélio Gonçalves, Arnulf Koeppen, Sebastian Kügler, Carlos Bandeira Duarte, Luís Pereira De AlmeidaAbstract:Machado–Joseph Disease is the most frequently found dominantly-inherited cerebellar ataxia. Over-repetition of a CAG trinucleotide in the MJD1 gene translates into a polyglutamine tract within the ataxin 3 protein, which upon proteolysis may trigger Machado–Joseph Disease. We investigated the role of calpains in the generation of toxic ataxin 3 fragments and pathogenesis of Machado–Joseph Disease. For this purpose, we inhibited calpain activity in mouse models of Machado–Joseph Disease by overexpressing the endogenous calpain-inhibitor calpastatin. Calpain blockage reduced the size and number of mutant ataxin 3 inclusions, neuronal dysfunction and neurodegeneration. By reducing fragmentation of ataxin 3, calpastatin overexpression modified the subcellular localization of mutant ataxin 3 restraining the protein in the cytoplasm, reducing aggregation and nuclear toxicity and overcoming calpastatin depletion observed upon mutant ataxin 3 expression. Our findings are the first in vivo proof that mutant ataxin 3 proteolysis by calpains mediates its translocation to the nucleus, aggregation and toxicity and that inhibition of calpains may provide an effective therapy for Machado–Joseph Disease. * Abbreviations : AAV : adeno-associated virus DARPP-32 : dopamine- and cyclic AMP-regulated neuronal phosphoprotein GFP : green fluorescent protein
Isabel Silveira - One of the best experts on this subject based on the ideXlab platform.
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neurologic findings in Machado Joseph Disease relation with Disease duration subtypes and cag n
JAMA Neurology, 2001Co-Authors: Laura Bannach Jardim, Isabel Silveira, Jorge Sequeiros, Maria Luiza Saraiva Pereira, Anabela Ferro, Roberto GiuglianiAbstract:Context: Machado-Joseph Disease (MJD), an autoso- mal dominant spinocerebellar degeneration caused by an expanded CAG repeat on chromosome 14q32.1, is a het- erogeneous disorder for clinical manifestations. The rea- sons for the wide range of neurologic findings in this dis- ease are poorly understood. Objective: To explain part of this heterogeneity through the association of the neurologic findings with sex, dis- ease duration, age of onset, clinical type, and size of CAG repeat expansion. Design: A case-control study. Setting: Ambulatory care. and ophthalmoplegia (P,.02). The most severe forms of nuclear ophthalmoplegia were associated with type 1 MJD, whereas those of supranuclear ophthalmoplegia were as- sociated with type 3 MJD (P,.001). It was also found that higher mean (CAG)n lengths were associated with worse degrees of the pyramidal syndrome and dystonia (P,.001). The presence and severity of nystagmus, eye- lid retraction, rigidity and/or bradykinesia, and optic at- rophy were not clearly associated with any of the pre- dictive variables under study. Conclusions: Disease duration can explain part of the heterogeneity of ataxia, dysarthria, dysphagia, fascicu- lations, pyramidal syndrome, and ophthalmoplegia, in MJD. Type 1 MJD was positively associated with nuclear ophthalmoplegia; type 3 MJD was positively associated with supranuclear ophthalmoplegia. Higher mean CAG lengths were found to correlate with the pyramidal syn- drome and dystonia. Nystagmus, eyelid retraction, ri- gidity and/or bradykinesia, and optic atrophy were hardly attributable to any known reason or variable. Arch Neurol. 2001;58:899-904
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fluorodopa and raclopride pet analysis of patients with Machado Joseph Disease
Neurology, 1997Co-Authors: Hitoshi Shinotoh, Isabel Silveira, B Thiessen, B J Snow, S Hashimoto, Patrick Macleod, Guy A Rouleau, Michael Schulzer, Donald B CalneAbstract:We performed [18F]6-fluoro-L-dopa (6-FD) and [11C]raclopride (RAC) PET studies in six patients with Machado-Joseph Disease (MJD) (age, 17 to 61 years; duration of illness, 3 to 10 years), normal controls (n = 10 in 6-FD-PET, n = 8 in RAC-PET), and patients with idiopathic parkinsonism (n = 15 in 6-FD-PET). The youngest patient with MJD had prominent dystonia and pyramidal features (type 1 MJD), whereas the remainder were prominently ataxic (types 2 and 3 MJD). Striatal RAC binding was normal in patients with MJD. Striatal 6-FD influx constants (Ki) were low in the range of idiopathic parkinsonism in two patients with MJD (youngest and oldest patients), whereas striatal Ki were normal in the remaining patients with MJD. The impairment of the nigrostriatal dopaminergic pathway did not correlate with the phenotype, CAG repeat length, Disease duration, or age of onset of patients with MJD. Our results suggest that striatal D2 receptors are normal and the nigral damage is diverse in MJD.
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somatic mosaicism in the central nervous system in spinocerebellar ataxia type 1 and Machado Joseph Disease
Annals of Neurology, 1996Co-Authors: I Lopescendes, Isabel Silveira, Claudia Gaspar, Patricia Maciel, Stephen J Kish, Yves Robitaille, Brent H ClarkAbstract:Spinocerebellar ataxia type 1 and Machado-Joseph Disease are two autosomal dominant cerebellar ataxias caused by expansions of unstable GAG repeats in the coding region of the causative genes. The selectivity of cell death and the resulting characteristic neuropathological features in each of these Diseases are not explained by the gene expression patterns. Since the repeat size correlates with age at onset and severity of these Diseases, somatic mosaicism, the result of mitotic instability of the GAG repeat, could be the basis for specificity of neurodegeneration ; brain structures with larger expanded repeats would be more severely affected. To study the association between neuropathological changes and somatic mosaicism of the GAG repeat size in the central nervous system of patients with these two ataxias, we determined the size of the (CAG)n expansion in 20 different regions of the brain, brainstem, cerebellum, and spinal cord from 3 patients with spinocerebellar ataxia type 1 and 3 with Machado-Joseph Disease ; these regions were selected for their differential neuropathological involvement in the two disorders. We observed a considerable homogeneity of repeat size ranges in all but 1 of the 20 regions examined : The cerebellar cortex showed slightly smaller (GAG)n tracts in all specimens from both groups of patients. Out results suggest that the pattern of repeat size mosaicism, similar in spinocerebellar ataxia type 1 and Machado-Joseph Disease, reflects the developmental pathways and cell composition of different central nervous system regions and is not the cause of selective cell death in these disorders.
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frequency of spinocerebellar ataxia type 1 dentatorubropallidoluysian atrophy and Machado Joseph Disease mutations in a large group of spinocerebellar ataxia patients
Web Science, 1996Co-Authors: Isabel Silveira, Claudia Gaspar, Paula Coutinho, Patricia Maciel, Stephen J Kish, Mi Botez, Iscia Lopescendes, Helio Ghizoni TeiveAbstract:The spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders varying in both clinical manifestations and mode of inheritance. Six different genes causing autosomal dominant SCA are mapped: SCA1, SCA2, Machado-Joseph Disease (MJD)/SCA3, SCA4, SCA5, and dentatorubropallidoluysian atrophy (DRPLA). Expansions of an unstable trinucleotide CAG repeat cause three of these disorders: SCA type 1 (SCA1), MJD, and DRPLA. We determine the frequency of the SCA1, DRPLA, and MJD mutations in a large group of unrelated SCA patients with various patterns of inheritance and different ethnic backgrounds. We studied 92 unrelated SCA patients. The frequency of the SCA1 mutation was 3% in the overall patient group and 10% in the non-Portuguese dominantly inherited SCA subgroup. We found that DRPLA mutation in only one Japanese patient, who was previously diagnosed with this Disease. We identified the MJD mutation in 41% of the overall patient group, which included 38 autosomal dominant kindreds of Portuguese origin; the frequency of the MJD mutation among the non-Portuguese dominantly inherited cases was 17%. These results suggest that SCA may be occasionally caused by the SCA1 mutation and rarely caused by the DRPLA mutation and that, to date, the MJD mutation seems to be the most common cause of dominantly inherited SCA. Finally, our results suggest that recessively inherited cases of SCA are not caused by the known trinucleotide repeat expansions.
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correlation between cag repeat length and clinical features in Machado Joseph Disease
American Journal of Human Genetics, 1995Co-Authors: Isabel Silveira, Claudia Gaspar, Paula Coutinho, Patricia Maciel, Anita L Destefano, Joao Radvany, David M DawsonAbstract:Machado-Joseph Disease (MJD) is associated with the expansion of a CAG trinucleotide repeat in a novel gene on 14q32.1. We confirmed the presence of this expansion in 156 MJD patients from 33 families of different geographic origins: 15 Portuguese Azorean, 2 Brazilian, and 16 North American of Portuguese Azorean descent. Normal chromosomes contain between 12 and 37 CAG repeats in the MJD gene, whereas MJD gene carriers have alleles within the expanded range of 62-84 CAG units. The distribution of expanded alleles and the gap between normal and expanded allele sizes is either inconsistent with a premutation hypothesis or most (if not all) of the alleles we studied descend from a common ancestor. There is a strong correlation between the expanded repeat size and the age at onset of the Disease as well as the clinical presentation. There is mild instability of the CAG tract length with transmission of the expanded alleles; both increase and decrease in size between parents and progeny occur, with larger variations in male than in female transmissions. Together, these effects can partly explain the variability of age at onset and of phenotypic features in MJD; however, other modifying factors must exist.
Henry L Paulson - One of the best experts on this subject based on the ideXlab platform.
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Machado Joseph Disease spinocerebellar ataxia type 3
Handbook of Clinical Neurology, 2012Co-Authors: Henry L PaulsonAbstract:Abstract Machado–Joseph Disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), may be the most common dominantly inherited ataxia in the world. Here I will review historical, clinical, neuropathological, genetic, and pathogenic features of MJD, and finish with a brief discussion of present, and possible future, treatment for this currently incurable disorder. Like many other dominantly inherited ataxias, MJD/SCA3 shows remarkable clinical heterogeneity, reflecting the underlying genetic defect: an unstable CAG trinucleotide repeat that varies in size among affected persons. This pathogenic repeat in MJD/SCA3 encodes an expanded tract of the amino acid glutamine in the Disease protein, which is known as ataxin-3. MJD/SCA3 is one of nine identified polyglutamine neurodegenerative Diseases which share features of pathogenesis centered on protein misfolding and accumulation. The specific properties of MJD/SCA3 and its Disease protein are discussed in light of what is known about the entire class of polyglutamine Diseases.
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the Machado Joseph Disease associated mutant form of ataxin 3 regulates parkin ubiquitination and stability
Human Molecular Genetics, 2011Co-Authors: Thomas M Durcan, Maria Kontogiannea, Henry L Paulson, Ana Djarmati, Thorhildur Thorarinsdottir, Lara Fallon, Aislinn J Williams, Tadeu Fantaneanu, Edward A FonAbstract:Machado–Joseph Disease (MJD), the most common dominantly inherited ataxia worldwide, is caused by a polyglutamine (polyQ) expansion in the deubiquitinating (DUB) enzyme ataxin-3. Interestingly, MJD can present clinically with features of Parkinsonism. In this study, we identify parkin, an E3 ubiquitin-ligase responsible for a common familial form of Parkinson’s Disease, as a novel ataxin-3 binding partner. The interaction between ataxin-3 and parkin is direct, involves multiple domains and is greatly enhanced by parkin selfubiquitination. Moreover, ataxin-3 deubiquitinates parkin directly in vitro and in cells. Compared with wildtype ataxin-3, MJD-linked polyQ-expanded mutant ataxin-3 is more active, possibly owing to its greater efficiency at DUB K27- and K29-linked Ub conjugates on parkin. Remarkably, mutant but not wild-type ataxin-3 promotes the clearance of parkin via the autophagy pathway. The finding is consistent with the reduction in parkin levels observed in the brains of transgenic mice over-expressing polyQ-expanded but not wild-type ataxin-3, raising the intriguing possibility that increased turnover of parkin may contribute to the pathogenesis of MJD and help explain some of its parkinsonian features.
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spinocerebellar ataxia type 3 Machado Joseph Disease severe destruction of the lateral reticular nucleus
Brain, 2002Co-Authors: C. Schultz, E R Brunt, Henry L Paulson, Heiko BraakAbstract:The lateral reticular nucleus (LRT) of the medulla oblongata is a precerebellar nucleus involved in proprioception and somatomotor automatisms. We investigated this nucleus in five individuals with clinically diagnosed and genetically confirmed spinocerebellar ataxia type 3 (SCA3, Machado–Joseph Disease). Polyethylene glycol‐embedded 100 µm thick sections stained for lipofuscin granules and Nissl material as well as Nissl‐stained paraffin‐embedded sections revealed severe destruction of the LRT in all SCA3 brains examined. Some of the few surviving neurones contained ataxin‐3‐immunopositive intranuclear inclusion bodies, as noted in other affected brain regions in SCA3. Along with the severe neuronal depletion, obvious astrogliosis was seen in the LRT of all SCA3 patients. The findings suggest that the LRT is a consistent target of the pathological process underlying SCA3. In view of its afferent and efferent connections, destruction of the LRT probably contributes to gait ataxia in individuals suffering from SCA3. Received December 19, 2001. Revised March 12, 2002. Second revision March 28, 2002. Accepted March 29, 2002
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Machado Joseph Disease gene product is a cytoplasmic protein widely expressed in brain
Annals of Neurology, 1997Co-Authors: Henry L Paulson, Sonal S Das, Peter B Crino, Matthew K Perez, Sonal C Patel, Denise Gotsdiner, Kenneth H Fischbeck, Randall N PittmanAbstract: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.
Nicole Déglon - One of the best experts on this subject based on the ideXlab platform.
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silencing mutant ataxin 3 rescues motor deficits and neuropathology in Machado Joseph Disease transgenic mice
PLOS ONE, 2013Co-Authors: Clévio Nóbrega, Hirokazu Hirai, David Albuquerque, Isabel Onofre, Nicole Déglon, Isabel Nascimentoferreira, Luís Pereira De AlmeidaAbstract:Machado-Joseph Disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly-inherited neurodegenerative disorder caused by the over-repetition of a CAG codon in the MJD1 gene. This expansion translates into a polyglutamine tract that confers a toxic gain-of-function to the mutant protein – ataxin-3, leading to neurodegeneration in specific brain regions, with particular severity in the cerebellum. No treatment able to modify the Disease progression is available. However, gene silencing by RNA interference has shown promising results. Therefore, in this study we investigated whether lentiviral-mediated allele-specific silencing of the mutant ataxin-3 gene, after Disease onset, would rescue the motor behavior deficits and neuropathological features in a severely impaired transgenic mouse model of MJD. For this purpose, we injected lentiviral vectors encoding allele-specific silencing-sequences (shAtx3) into the cerebellum of Diseased transgenic mice expressing the targeted C-variant of mutant ataxin-3 present in 70% of MJD patients. This variation permits to discriminate between the wild-type and mutant forms, maintaining the normal function of the wild-type allele and silencing only the mutant form. Quantitative analysis of rotarod performance, footprint and activity patterns revealed significant and robust alleviation of gait, balance (average 3-fold increase of rotarod test time), locomotor and exploratory activity impairments in shAtx3-injected mice, as compared to control ones injected with shGFP. An important improvement of neuropathology was also observed, regarding the number of intranuclear inclusions, calbindin and DARPP-32 immunoreactivity, fluorojade B and Golgi staining and molecular and granular layers thickness. These data demonstrate for the first time the efficacy of gene silencing in blocking the MJD-associated motor-behavior and neuropathological abnormalities after the onset of the Disease, supporting the use of this strategy for therapy of MJD.
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calpastatin mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis nuclear localization and aggregation relieving Machado Joseph Disease
Brain, 2012Co-Authors: Ana T Simões, Nicole Déglon, Nélio Gonçalves, Arnulf Koeppen, Sebastian Kügler, Carlos Bandeira Duarte, Luís Pereira De AlmeidaAbstract:Machado–Joseph Disease is the most frequently found dominantly-inherited cerebellar ataxia. Over-repetition of a CAG trinucleotide in the MJD1 gene translates into a polyglutamine tract within the ataxin 3 protein, which upon proteolysis may trigger Machado–Joseph Disease. We investigated the role of calpains in the generation of toxic ataxin 3 fragments and pathogenesis of Machado–Joseph Disease. For this purpose, we inhibited calpain activity in mouse models of Machado–Joseph Disease by overexpressing the endogenous calpain-inhibitor calpastatin. Calpain blockage reduced the size and number of mutant ataxin 3 inclusions, neuronal dysfunction and neurodegeneration. By reducing fragmentation of ataxin 3, calpastatin overexpression modified the subcellular localization of mutant ataxin 3 restraining the protein in the cytoplasm, reducing aggregation and nuclear toxicity and overcoming calpastatin depletion observed upon mutant ataxin 3 expression. Our findings are the first in vivo proof that mutant ataxin 3 proteolysis by calpains mediates its translocation to the nucleus, aggregation and toxicity and that inhibition of calpains may provide an effective therapy for Machado–Joseph Disease. * Abbreviations : AAV : adeno-associated virus DARPP-32 : dopamine- and cyclic AMP-regulated neuronal phosphoprotein GFP : green fluorescent protein
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Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado-Joseph Disease.
Brain, 2011Co-Authors: Isabel Nascimento-ferreira, Tiago Santos-ferreira, Lígia Sousa-ferreira, Gwennaëlle Auregan, Isabel Onofre, Sandro Alves, Noëlle Dufour, Veronica F. Colomer Gould, Nicole DéglonAbstract:Machado–Joseph Disease, also known as spinocerebellar ataxia type 3, is the most common of the dominantly inherited ataxias worldwide and is characterized by mutant ataxin-3 misfolding, intracellular accumulation of aggregates and neuronal degeneration. Here we investigated the implication of autophagy, the major pathway for organelle and protein turnover, in the accumulation of mutant ataxin-3 aggregates and neurodegeneration found in Machado–Joseph Disease and we assessed whether specific stimulation of this pathway could mitigate the Disease. Using tissue from patients with Machado–Joseph Disease, transgenic mice and a lentiviral-based rat model, we found an abnormal expression of endogenous autophagic markers, accumulation of autophagosomes and decreased levels of beclin-1, a crucial protein in the early nucleation step of autophagy. Lentiviral vector-mediated overexpression of beclin-1 led to stimulation of autophagic flux, mutant ataxin-3 clearance and overall neuroprotective effects in neuronal cultures and in a lentiviral-based rat model of Machado–Joseph Disease. These data demonstrate that autophagy is a key degradation pathway, with beclin-1 playing a significant role in alleviating Machado–Joseph Disease pathogenesis. * Abbreviations : Atg : autophagic related protein DARPP-32 : dopamine-and-cyclic AMP-regulated phosphoprotein of 32 kDa p62 : sequestosome 1/p62 protein
