Spinocerebellar ataxia type 3/Machado-Joseph disease （SCA3/MJD） is a progressive, currently untreatable and ultimately fatal ataxic disorder that belongs to the group of neurological disorders known as CAG-repeat or...Spinocerebellar ataxia type 3/Machado-Joseph disease （SCA3/MJD） is a progressive, currently untreatable and ultimately fatal ataxic disorder that belongs to the group of neurological disorders known as CAG-repeat or polyglutamine diseases. Here, we present the first prenatal diagnosis of SCA3/MJD in China's Mainland in a woman who was known to carry an expanded CAG-trinucleotide repeat in the MJD1 gene. After evaluating motivation and psychological tolerance of the couple, amniocentesis was performed after 14 weeks of gestation. Polymerase chain reactions followed by T-vector cloning and direct sequencing were employed to evaluate the CAG-repeat number of the fetal MJD1 gene. We identified a truncated CAG expansion of 78 repeats in the MJD1 gene of the fetus compared with 81 repeats in his mother.展开更多
This study reports a case of a 75-year-old female Machado-Joseph disease patient exhibiting unstable walking and inaccurate hand holding for 8 months, which progressively worsened. Physical examination on admission sh...This study reports a case of a 75-year-old female Machado-Joseph disease patient exhibiting unstable walking and inaccurate hand holding for 8 months, which progressively worsened. Physical examination on admission showed cerebellar ataxia and a history of hypertension. Crania MRI demonstrated cerebellar and brain stem atrophy. Gene analysis showed abnormal amplification of the CAG trinucleotide repeat in exon 10 of the ataxin-3 （ATXN3） gene, resulting in 70-81 CAG repeats in the patient, with a significant positive family history.展开更多
<div style="text-align:justify;"> <span style="font-family:Verdana;">Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodege...<div style="text-align:justify;"> <span style="font-family:Verdana;">Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodegenerative disorder that predominantly involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. SCA3 presents strong phenotypic heterogeneity and its causative mutation of SCA3 consists of an expansion of a CAG tract in exon 10 of the <em>ATXN3</em> gene, situated at 14q32.1. The <em>ATXN3</em> gene is ubiquitously expressed in neuronal and non-neuronal tissues, and also participates in cellular protein quality control pathways. Mutated <em>ATXN3</em> alleles present about 45 to 87CAG repeats, which result in an expanded polyglutamine tract in ataxin-3. After mutation, the polyQ tract reaches the pathological threshold (about 50 glutamine residues);the protein is considered that it might gain a neurotoxic function through some unclear mechanisms. We reviewed the literature on the pathogenesis and therapeutic strategies of spinocerebellar ataxia type 3 patients. Conversion of the expanded protein is possible by enhancing protein refolding and degradation or preventing proteolytic cleavage and prevents the protein to reach the site of toxicity by altering its ability to translocate between the nucleus and cytoplasm. Proteasomal degradation and enhancing autophagic aggregate clearance are currently proposed remarkable therapy. In spite of extensive research, the molecular mechanisms of cellular toxicity resulting from mutant ataxin-3 remain no preventive treatment is currently available. These therapeutic strategies might be able to improve sign symptoms of SCA3 as well as slow the disease progression.</span> </div>展开更多
Objective Machado-Joseph disease （MJD）/Spinocerebellar ataxia type 3 （SCA3） is an autosomal dominant neurodegenerative disorder caused by an expansion of polyglutamine tract near the C-terminus of the MJD1 gene pr...Objective Machado-Joseph disease （MJD）/Spinocerebellar ataxia type 3 （SCA3） is an autosomal dominant neurodegenerative disorder caused by an expansion of polyglutamine tract near the C-terminus of the MJD1 gene product, ataxin-3. The precise mechanism of the MJD/SCA3 pathogenesis remains unclear. A growing body of evidence demonstrates that phosphorylation plays an important role in the pathogenesis of many neurodegenerative diseases. However, few kinases are known to phosphorylate ataxin-3. The present study is to explore whether ataxin-3 is a substrate of casein kinase 2 （CK2）. Methods The interaction between ataxin-3 and CK2 was identified by glutathione S-transferase （GST） pull-down assay and co-immunoprecipition assay. The phosphorylation of ataxin-3 by CK2 was measured by in vitro phosphorylation assays. Results （1） Both wild type and expanded ataxin-3 interacted with CK2α and CK2β in vitro. （2） In 293 cells, both wild type and expanded ataxin-3 interacted with CK2β, but not CK2α. （3） CK2 phosphorylated wild type and expanded ataxin-3. Conclusion Ataxin-3 is a substrate of protein kinase CK2.展开更多
目的:探讨氢质子波谱(proton magnetic resonance spectroscopy,~1H-MRS)在脊髓小脑型共济失调3型/马查多–约瑟夫病(hereditary spinocerebellar ataxias 3 and Machado-Joseph,SCA3/MJD)诊断中的价值,同时探讨其与临床病程评分之间的...目的:探讨氢质子波谱(proton magnetic resonance spectroscopy,~1H-MRS)在脊髓小脑型共济失调3型/马查多–约瑟夫病(hereditary spinocerebellar ataxias 3 and Machado-Joseph,SCA3/MJD)诊断中的价值,同时探讨其与临床病程评分之间的联系。方法:SCA3/MJD起病患者、SCA3/MJD未起病患者及年龄匹配健康志愿者进行~1H-MRS检查,经数据后处理获得N–乙酰天门冬氨酸(N-acetylaspartate,NAA),肌酸(creatine,Cr),胆碱(choline-containing compounds,Cho),肌醇(myo-inositol,m I)值及NAA/Cr,Cho/Cr,m I/Cr比值。将以上数据进行对比研究;同时对于SCA3/MJD起病患者进行国际协作共济失调评估量表(International Cooperative Ataxia Rating Scale,ICARS)及共济失调等级量表(Scale for the Assessment and Rating of Ataxia,SARA)评估,计算NAA/Cr,Cho/Cr,m I/Cr比值与临床评分之间的相关性。结果:SCA3/MJD起病患者在桥脑及齿状核的NAA/Cr值较正常对照组明显减低。SCA3/MJD起病患者小脑齿状核NAA/Cr值与ICARS评分有明显相关性。结论:SCA3/MJD的病变主要位于小脑及脑干,ICARS评分与小脑病变的程度有相关性,能较好地反映临床表现的轻重程度。~1H-MRS对于SCA3/MJD的诊断有一定的应用前景。展开更多
目的:探讨弥散加权成像(diffusion weighted imaging,DWI)在遗传性脊髓小脑型共济失调3型/马查多-约瑟夫病(hereditary spinocerebellar ataxia 3 and the Machado Joseph disease,SCA3/MJD)及遗传性痉挛性截瘫4型(hereditary spastic p...目的:探讨弥散加权成像(diffusion weighted imaging,DWI)在遗传性脊髓小脑型共济失调3型/马查多-约瑟夫病(hereditary spinocerebellar ataxia 3 and the Machado Joseph disease,SCA3/MJD)及遗传性痉挛性截瘫4型(hereditary spastic paraplegia 4,SPG4)的诊断及鉴别诊断中的价值。方法:对13例SPG4患者,30例SCA3/MJD及27名年龄匹配的健康志愿者进行DWI检查,经数据后处理获得了表观扩散系数(apparent diffusion coefficient,ADC)值。将以上数据分组进行对比研究。结果:SCA3/MJD起病患者的ADC值在中央前回、内囊后肢、大脑脚、桥脑、小脑皮层及小脑白质区域较正常对照组升高。SCA3/MJD未起病患者的ADC值仅在小脑齿状核位置较正常对照组增高。SCA3/MJD起病患者仅在小脑皮层较SCA3/MJD未起病患者ADC值明显升高;SCA3/MJD起病患者的ADC值在内囊后肢、小脑皮层、小脑白质及桥脑较SPG4患者明显增高。在中央前回,SPG4患者的ADC值较正常对照组明显增高。结论:DWI对于SCA3/MJD与SPG4的鉴别诊断有一定的应用前景。展开更多
Objective Machado-Joseph disease （MJD）, also known as spinocerebellar ataxia type 3 （SCA3）, is a dominant neurodegenerative disorder caused by an expansion of the polyglutamine （polyQ） tract in MJD-1 gene produc...Objective Machado-Joseph disease （MJD）, also known as spinocerebellar ataxia type 3 （SCA3）, is a dominant neurodegenerative disorder caused by an expansion of the polyglutamine （polyQ） tract in MJD-1 gene product, ataxin-3 （AT3）. This disease is characterized by the formation of intraneuronal inclusions, but the mechanism underlying their formation is still poorly understood. The present study is to explore the relationship between wild type （WT） AT3 and polyQ expanded AT3. Methods Mouse neuroblastoma （N2a） cells or HEK293 cells were co-transfected with WTAT3 and different truncated forms of expanded AT3. The expressions of WT AT3 and the truncated forms of expanded AT3 were detected by Western blotting, and observed by an inverted fluorescent microscope. The interactions between AT3 and different truncated forms of expanded AT3 were detected by immunoprecipitation and GST pull-down assays. Results Using fluorescent microscope, we observed that the truncated forms of expanded AT3 aggregate in transfected cells, and the full-length WT AT3 is recruited onto the aggregates. However, no aggregates were observed in cells transfected with the truncated forms of WT AT3. Immunoprecipitation and GST pull-down analyses indicate that WT AT3 interacts with the truncated AT3 in a polyQ length-dependent manner. Conclusion WT AT3 deposits in the aggregation that was formed by polyQ expanded AT3, which suggests that the formation of AT3 aggregation may affect the normal function of WT AT3 and increase polyQ protein toxicity in MJD.展开更多
基金grants from the National Science and Technology Pillar Program in the Eleventh Five-year Plan Period, No. 2006BAI05A07the Major State Basic Research Development Program of China (973 Program), No. 2006cb500700+5 种基金the National Key Technologies Research and Development Program of China, No. 2004BA720A03the National Natural Science Foundation of China, No. 30871354, 30710303061 and 30470619the Key Project in the Natural Science Foundation of Hunan Province, No. 08JJ3048the Natural Science Foundation of Hunan Province, No. 11JJ5071the Science and Technology Planning Project of Hunan Province, No. 2009SK3172the Graduate Degree Thesis Innovation Foundation of Central South University, No. 2008yb030
文摘Spinocerebellar ataxia type 3/Machado-Joseph disease （SCA3/MJD） is a progressive, currently untreatable and ultimately fatal ataxic disorder that belongs to the group of neurological disorders known as CAG-repeat or polyglutamine diseases. Here, we present the first prenatal diagnosis of SCA3/MJD in China's Mainland in a woman who was known to carry an expanded CAG-trinucleotide repeat in the MJD1 gene. After evaluating motivation and psychological tolerance of the couple, amniocentesis was performed after 14 weeks of gestation. Polymerase chain reactions followed by T-vector cloning and direct sequencing were employed to evaluate the CAG-repeat number of the fetal MJD1 gene. We identified a truncated CAG expansion of 78 repeats in the MJD1 gene of the fetus compared with 81 repeats in his mother.
基金funded by Fengxian District Science Technology Commission Foundation of Shanghai,No.2010-101101,2011-110
文摘This study reports a case of a 75-year-old female Machado-Joseph disease patient exhibiting unstable walking and inaccurate hand holding for 8 months, which progressively worsened. Physical examination on admission showed cerebellar ataxia and a history of hypertension. Crania MRI demonstrated cerebellar and brain stem atrophy. Gene analysis showed abnormal amplification of the CAG trinucleotide repeat in exon 10 of the ataxin-3 （ATXN3） gene, resulting in 70-81 CAG repeats in the patient, with a significant positive family history.
文摘<div style="text-align:justify;"> <span style="font-family:Verdana;">Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodegenerative disorder that predominantly involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. SCA3 presents strong phenotypic heterogeneity and its causative mutation of SCA3 consists of an expansion of a CAG tract in exon 10 of the <em>ATXN3</em> gene, situated at 14q32.1. The <em>ATXN3</em> gene is ubiquitously expressed in neuronal and non-neuronal tissues, and also participates in cellular protein quality control pathways. Mutated <em>ATXN3</em> alleles present about 45 to 87CAG repeats, which result in an expanded polyglutamine tract in ataxin-3. After mutation, the polyQ tract reaches the pathological threshold (about 50 glutamine residues);the protein is considered that it might gain a neurotoxic function through some unclear mechanisms. We reviewed the literature on the pathogenesis and therapeutic strategies of spinocerebellar ataxia type 3 patients. Conversion of the expanded protein is possible by enhancing protein refolding and degradation or preventing proteolytic cleavage and prevents the protein to reach the site of toxicity by altering its ability to translocate between the nucleus and cytoplasm. Proteasomal degradation and enhancing autophagic aggregate clearance are currently proposed remarkable therapy. In spite of extensive research, the molecular mechanisms of cellular toxicity resulting from mutant ataxin-3 remain no preventive treatment is currently available. These therapeutic strategies might be able to improve sign symptoms of SCA3 as well as slow the disease progression.</span> </div>
基金the National Natural Sciences Foundation of China (No. 30770664)a grant from Educational Committee of Anhui Province, China (No. ZD2008008-2).
文摘Objective Machado-Joseph disease （MJD）/Spinocerebellar ataxia type 3 （SCA3） is an autosomal dominant neurodegenerative disorder caused by an expansion of polyglutamine tract near the C-terminus of the MJD1 gene product, ataxin-3. The precise mechanism of the MJD/SCA3 pathogenesis remains unclear. A growing body of evidence demonstrates that phosphorylation plays an important role in the pathogenesis of many neurodegenerative diseases. However, few kinases are known to phosphorylate ataxin-3. The present study is to explore whether ataxin-3 is a substrate of casein kinase 2 （CK2）. Methods The interaction between ataxin-3 and CK2 was identified by glutathione S-transferase （GST） pull-down assay and co-immunoprecipition assay. The phosphorylation of ataxin-3 by CK2 was measured by in vitro phosphorylation assays. Results （1） Both wild type and expanded ataxin-3 interacted with CK2α and CK2β in vitro. （2） In 293 cells, both wild type and expanded ataxin-3 interacted with CK2β, but not CK2α. （3） CK2 phosphorylated wild type and expanded ataxin-3. Conclusion Ataxin-3 is a substrate of protein kinase CK2.
文摘目的:探讨氢质子波谱(proton magnetic resonance spectroscopy,~1H-MRS)在脊髓小脑型共济失调3型/马查多–约瑟夫病(hereditary spinocerebellar ataxias 3 and Machado-Joseph,SCA3/MJD)诊断中的价值,同时探讨其与临床病程评分之间的联系。方法:SCA3/MJD起病患者、SCA3/MJD未起病患者及年龄匹配健康志愿者进行~1H-MRS检查,经数据后处理获得N–乙酰天门冬氨酸(N-acetylaspartate,NAA),肌酸(creatine,Cr),胆碱(choline-containing compounds,Cho),肌醇(myo-inositol,m I)值及NAA/Cr,Cho/Cr,m I/Cr比值。将以上数据进行对比研究;同时对于SCA3/MJD起病患者进行国际协作共济失调评估量表(International Cooperative Ataxia Rating Scale,ICARS)及共济失调等级量表(Scale for the Assessment and Rating of Ataxia,SARA)评估,计算NAA/Cr,Cho/Cr,m I/Cr比值与临床评分之间的相关性。结果:SCA3/MJD起病患者在桥脑及齿状核的NAA/Cr值较正常对照组明显减低。SCA3/MJD起病患者小脑齿状核NAA/Cr值与ICARS评分有明显相关性。结论:SCA3/MJD的病变主要位于小脑及脑干,ICARS评分与小脑病变的程度有相关性,能较好地反映临床表现的轻重程度。~1H-MRS对于SCA3/MJD的诊断有一定的应用前景。
基金the National Natural Sciences Foundation of China (No.30770664)a grant from Anhui Educational Committee(No. ZD2008008-2)
文摘Objective Machado-Joseph disease （MJD）, also known as spinocerebellar ataxia type 3 （SCA3）, is a dominant neurodegenerative disorder caused by an expansion of the polyglutamine （polyQ） tract in MJD-1 gene product, ataxin-3 （AT3）. This disease is characterized by the formation of intraneuronal inclusions, but the mechanism underlying their formation is still poorly understood. The present study is to explore the relationship between wild type （WT） AT3 and polyQ expanded AT3. Methods Mouse neuroblastoma （N2a） cells or HEK293 cells were co-transfected with WTAT3 and different truncated forms of expanded AT3. The expressions of WT AT3 and the truncated forms of expanded AT3 were detected by Western blotting, and observed by an inverted fluorescent microscope. The interactions between AT3 and different truncated forms of expanded AT3 were detected by immunoprecipitation and GST pull-down assays. Results Using fluorescent microscope, we observed that the truncated forms of expanded AT3 aggregate in transfected cells, and the full-length WT AT3 is recruited onto the aggregates. However, no aggregates were observed in cells transfected with the truncated forms of WT AT3. Immunoprecipitation and GST pull-down analyses indicate that WT AT3 interacts with the truncated AT3 in a polyQ length-dependent manner. Conclusion WT AT3 deposits in the aggregation that was formed by polyQ expanded AT3, which suggests that the formation of AT3 aggregation may affect the normal function of WT AT3 and increase polyQ protein toxicity in MJD.
