Genomes and Genes
machado joseph disease
Summary: A dominantly-inherited ATAXIA first described in people of Azorean and Portuguese descent, and subsequently identified in Brazil, Japan, China, and Australia. This disorder is classified as one of the SPINOCEREBELLAR ATAXIAS (Type 3) and has been associated with a mutation of the MJD1 gene on chromosome 14. Clinical features include progressive ataxia, DYSARTHRIA, postural instability, nystagmus, eyelid retraction, and facial FASCICULATIONS. DYSTONIA is prominent in younger patients (referred to as Type I Machado-Joseph Disease). Type II features ataxia and ocular signs; Type III features MUSCULAR ATROPHY and a sensorimotor neuropathy; and Type IV features extrapyramidal signs combined with a sensorimotor neuropathy. (From Clin Neurosci 1995;3(1):17-22; Ann Neurol 1998 Mar;43(3):288-96)
Publications177 found, 100 shown here
- CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1Y Kawaguchi
Department of Pharmacology, Kyoto University Faculty of Medicine, Japan
Nat Genet 8:221-8. 1994..Southern blot analyses and genomic cloning demonstrates the existence of related genes. These results raise the possibility that similar abnormalities in related genes may give rise to diseases similar to MJD...
- Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidenceUlrike Bichelmeier
Department of Medical Genetics, University of Tubingen, D 72076 Tubingen, Germany
J Neurosci 27:7418-28. 2007..These studies indicate that nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3 in vivo...
- Study of subcellular localization and proteolysis of ataxin-3Chiara Pozzi
Dipartimento di Biotecnologie e Bioscienze, Universita di Milano Bicocca, P za della Scienza 2, 20126 Milan, Italy
Neurobiol Dis 30:190-200. 2008..This may play a role in the pathogenesis, hampering degradation of aggregation-prone expanded AT-3. In addition, autolytic cleavage was apparently not involved in AT-3 proteolysis...
- Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivoH Ikeda
Department of Pharmacology, Kyoto University Faculty of Medicine, Japan
Nat Genet 13:196-202. 1996..Our results demonstrate the potential involvement of the expanded polyglutamine as the common aetiological agent for inherited neurodegenerative diseases with CAG expansions...
- Caspase-mediated proteolysis of the polyglutamine disease protein ataxin-3Sarah J Shoesmith Berke
Neuroscience Graduate Program and Department of Neurology, University of Iowa, Iowa City, Iowa 52242, USA
J Neurochem 89:908-18. 2004..Finally, caspase-mediated cleavage of expanded ataxin-3 resulted in increased ataxin-3 aggregation, suggesting a potential role for caspase-mediated proteolysis in spinocerebellar ataxia type-3 pathogenesis...
- Elucidation of ataxin-3 and ataxin-7 function by integrative bioinformaticsHartmut Scheel
Bioinformatics Group, Memorec Biotec GmbH, Koln, Germany
Hum Mol Genet 12:2845-52. 2003..Ataxin-3, the protein mutated in Machado Joseph Disease (SCA3), belongs to a novel group of cysteine-proteases and is predicted to be active against ubiquitin ..
- CREB-binding protein modulates repeat instability in a Drosophila model for polyQ diseaseJoonil Jung
Department of Biology, University of Pennsylvania, Philadelphila, PA 19104, USA
Science 315:1857-9. 2007..Pharmacological treatment to normalize acetylation suppressed instability. Thus, toxic consequences of pathogenic polyQ protein may include enhancing repeat instability...
- Trinucleotide expansion within the MJD1 gene presents clinically as spinocerebellar ataxia and occurs most frequently in German SCA patientsL Schols
Department of Neurology, St Josef Hospital, Bochum, Germany
Hum Mol Genet 4:1001-5. 1995..These results demonstrate that the MJD mutation causes the disease phenotype of most SCA patients in Germany...
- Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanismJohn M Warrick
Department of Biology, University of Pennsylvania, 415 South University Avenue, Philadelphia, Pennsylvania 19104, USA
Mol Cell 18:37-48. 2005..Our results highlight the critical importance of host protein function in SCA3 disease and a potential therapeutic role of ataxin-3 activity for polyglutamine disorders...
- Dominantly inherited ataxias: lessons learned from Machado-Joseph disease/spinocerebellar ataxia type 3Henry L Paulson
Department of Neurology, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA
Semin Neurol 27:133-42. 2007..Also discussed are current and future therapeutic opportunities for MJD/SCA3 in particular, many of which have relevance to other SCAs...
- Asian origin for the worldwide-spread mutational event in Machado-Joseph diseaseSandra Martins
Instituto de Patologia e Imunologia Molecular da Universidade do Porto and Faculdade de Ciências, University of Porto, Porto, Portugal
Arch Neurol 64:1502-8. 2007..Machado-Joseph disease is the most frequent dominant ataxia worldwide. Despite its frequency and presence in many populations, only 2 founder mutations have been suggested to explain its current geographic distribution...
- Allele-specific RNA silencing of mutant ataxin-3 mediates neuroprotection in a rat model of Machado-Joseph diseaseSandro Alves
Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
PLoS ONE 3:e3341. 2008..These data demonstrate that RNAi has potential for use in MJD treatment and constitute the first proof-of-principle for allele-specific silencing in the central nervous system...
- Allele-specific silencing of dominant disease genesVictor M Miller
Department of Neurology, Graduate Program in Genetics, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA 52242, USA
Proc Natl Acad Sci U S A 100:7195-200. 2003..These studies establish that siRNA can be engineered to silence disease genes differing by a single nucleotide and highlight a key role for SNPs in extending the utility of siRNA in dominantly inherited disorders...
- Founder haplotype for Machado-Joseph disease in the Indian population: novel insights from history and polymorphism studiesUma Mittal
Functional Genomics Unit, Institute of Genomics and Integrative Biology, New Delhi, India
Arch Neurol 62:637-40. 2005..The ACA haplotype is associated with 72% of the expanded repeats in Machado-Joseph disease (MJD) worldwide and has been traced to a Portuguese ancestry. It is present in only 5% of the normal chromosomes in the Portuguese population...
- Spinocerebellar ataxia type 3 (SCA3): thalamic neurodegeneration occurs independently from thalamic ataxin-3 immunopositive neuronal intranuclear inclusionsUdo Rüb
Institute for Clinical Neuroanatomy, Johann Wolfgang Goethe Univeristy, Frankfurt Main, Germany
Brain Pathol 16:218-27. 2006..This lack of correlation may suggest that ataxin-3 immunopositive NI are not immediately decisive for the fate of affected nerve cells but rather represent unspecific and pathognomonic morphological markers of SCA3...
- Improvement in the molecular diagnosis of Machado-Joseph diseaseP Maciel
UnIGENe, IBMC, Universidade do Porto, 4150-180 Porto, Portugal
Arch Neurol 58:1821-7. 2001..These strategies, developed to overcome the practical difficulties mostly in the presymptomatic and prenatal diagnosis of MJD, should prove useful for other polyglutamine-related disorders...
- Guidelines for the pathoanatomical examination of the lower brain stem in ingestive and swallowing disorders and its application to a dysphagic spinocerebellar ataxia type 3 patientU Rüb
Department of Clinical Neuroanatomy, Johann Wolfgang Goethe University, Frankfurt, Germany
Neuropathol Appl Neurobiol 29:1-13. 2003....
- [Analysis and application of SCA1 and SCA3/MJD gene CAG repeats in Han population in Northeastern China]Miao Jiang
Department of Medical Genetics, China Medical University, Shenyang, Liaoning, PR China
Zhonghua Yi Xue Yi Chuan Xue Za Zhi 21:83-5. 2004....
- Frequency of spinocerebellar ataxia mutations in the Kinki district of JapanR Matsumura
Department of Neurology, Nishi Nara National Hospital, Hichijo, Nara
Acta Neurol Scand 107:38-41. 2003..To determine the frequencies of spinocerebellar ataxias (SCAs) in the Kinki district, the western part of the main island of Japan...
- A mutant ataxin-3 putative-cleavage fragment in brains of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentrationDaniel Goti
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
J Neurosci 24:10266-79. 2004....
- Population genetics of wild-type CAG repeats in the Machado-Joseph disease gene in PortugalM Lima
Center of Research in Natural Resources CIRN, University of the Azores, Ponta Delgada, Portugal
Hum Hered 60:156-63. 2005....
- Absence of spinocerebellar ataxia type 3/Machado-Joseph disease within ataxic patients in the Czech populationP O Bauer
Neurogenetic Centre of the Institute of Biology and Medical Genetics, Department of Child Neurology, 2nd Medical Faculty of Charles University and Faculty Hospital Motol, Prague, Czech Republic
Eur J Neurol 12:851-7. 2005..9). We postulate that the absence of SCA3 in the Czech population might be explained by the lack of large normal alleles and consequently a relatively small reservoir for aberrant CAG expansions at the SCA3 locus...
- The polyglutamine neurodegenerative protein ataxin 3 regulates aggresome formationBarrington G Burnett
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6084, USA
Proc Natl Acad Sci U S A 102:4330-5. 2005..These same mutations decrease the association of AT3 and dynein. These data indicate that the deubiquitylating activity of AT3 and its ubiquitin interacting motifs as well play essential roles in CFTRDeltaF508 aggresome formation...
- Variation of CAG repeats and two intragenic polymorphisms at SCA3 locus among Machado-Joseph disease/SCA3 patients and diverse normal populations from eastern IndiaB Chattopadhyay
Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, Kolkata, India
Acta Neurol Scand 108:407-14. 2003..To explain the low prevalence of the disease among SCA patients from eastern India, we analysed CAG repeats and two bi-allelic intragenic markers at SCA3 locus among 412 normal individuals and 10 patients...
- Degeneration of the central vestibular system in spinocerebellar ataxia type 3 (SCA3) patients and its possible clinical significanceU Rüb
Institute for Clinical Neuroanatomy, Johann Wolfgang Goethe University, Theodor Stern Kai, Frankfurt Main, Germany
Neuropathol Appl Neurobiol 30:402-14. 2004..The reported lesions can help to explain the truncal and postural instability as well as the impaired optokinetic nystagmus, vestibulo-ocular reaction, and horizontal gaze-holding present in SCA3 cases...
- Involvement of the cerebral cortex and autonomic ganglia in Machado-Joseph diseaseM Yamada
Department of Pathology, Brain Research Institute, Niigata University, Japan
Acta Neuropathol 101:140-4. 2001..These lesions, newly recognized by polyglutamine immunohistochemistry, may be responsible for the cerebral cortical dysfunctions or autonomic abnormalities pointed out in MJD patients by the recent clinical and neuroradiological studies...
- New insights into the pathoanatomy of spinocerebellar ataxia type 3 (Machado-Joseph disease)Udo Rüb
Institute for Clinical Neuroanatomy, J W Goethe University, D 60590 Frankfurt Main, Germany
Curr Opin Neurol 21:111-6. 2008..This review summarizes recent neuropathological findings in spinocerebellar ataxia type 3 and discusses their relevance for clinical neurology...
- Calpain inhibition is sufficient to suppress aggregation of polyglutamine-expanded ataxin-3Annette Haacke
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany
J Biol Chem 282:18851-6. 2007..These findings suggest a critical role of calpains in the pathogenesis of Spinocerebellar ataxia type 3...
- Study of three intragenic polymorphisms in the Machado-Joseph disease gene (MJD1) in relation to genetic instability of the (CAG)n tractP Maciel
Centre for Research in Neuroscience, McGill University, Canada
Eur J Hum Genet 7:147-56. 1999....
- Immunohistochemical study of neuronal intranuclear and cytoplasmic inclusions in Machado-Joseph diseaseMasahiro Hayashi
Department of Neuropsychiatry, National Hokuriku Hospital, Nobusue, Jouhana machi, Toyama, Japan
Psychiatry Clin Neurosci 57:205-13. 2003..It is noteworthy that the nuclei of the spinal motoneurons lacked 1C2-positive immunoreactivity, so that ubiquitination of 1C2-positive structures is presumed to occur late in the course of the disease...
- Spinocerebellar ataxia type 3 phenotypically resembling parkinson disease in a black familyK Gwinn-Hardy
Mayo Clinic Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224, USA
Arch Neurol 58:296-9. 2001..However, classically, atypical features, including pyramidal and cerebellar signs, peripheral neuropathy, and/or anterior horn cell dysfunction, are also seen. Levodopa responsiveness is unusual in this disorder...
- Homozygosity enhances severity in spinocerebellar ataxia type 3Daniel R Carvalho
Genetic Unit, Sarah Network of Rehabilitation Hospitals, Brasilia, DF, Brazil
Pediatr Neurol 38:296-9. 2008..This case supports the conclusion that homozygosity aggravates the clinical phenotype. Loss of function of the normal expressed ataxin-3, or possibly aggregation of ataxin-3, may be implicated in disease mechanism...
- Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brainH L Paulson
Department of Pharmacology, University of Pennsylvania, Philadelphia 19104, USA
Ann Neurol 41:453-62. 1997..The restricted expression of ataxin-3 in certain regions, however, may influence the pattern of neurodegeneration and provide clues to the protein's function...
- Identification of chemical inhibitors to human tissue transglutaminase by screening existing drug librariesThung S Lai
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
Chem Biol 15:969-78. 2008..The TGM2 inhibitors we discovered may serve as valuable lead compounds for the development of orally active TGM2 inhibitors to treat human diseases...
- A mutant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic miceVeronica F Colomer Gould
Department of Psychiatry, Johns Hopkins University School of Medicine, 600 N Wolfe Street, Meyer Research Building, Room 4 158, Baltimore, MD 21287, USA
Neurobiol Dis 27:362-9. 2007..Our results support the toxic fragment hypothesis and narrow the mutant ataxin-3 cleavage site to the N-terminus of amino acid 190...
- Spinocerebellar ataxias types 2 and 3: degeneration of the pre-cerebellar nuclei isolates the three phylogenetically defined regions of the cerebellumU Rüb
Institute of Clinical Neuroanatomy, J W Goethe University, Frankfurt Main, Germany
J Neural Transm 112:1523-45. 2005....
- Recruitment and the role of nuclear localization in polyglutamine-mediated aggregationM K Perez
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
J Cell Biol 143:1457-70. 1998..In addition, we demonstrate that the nuclear environment may be critical for seeding polyglutamine aggregates...
- The p62 antibody reveals various cytoplasmic protein aggregates in spinocerebellar ataxia type 6K Seidel
Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Germany
Clin Neuropathol 28:344-9. 2009....
- Ataxin-3 interactions with rad23 and valosin-containing protein and its associations with ubiquitin chains and the proteasome are consistent with a role in ubiquitin-mediated proteolysisEllen W Doss-Pepe
Department of Biochemistry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA
Mol Cell Biol 23:6469-83. 2003....
- Functional genomics and biochemical characterization of the C. elegans orthologue of the Machado-Joseph disease protein ataxin-3Ana João Rodrigues
Life and Health Sciences Research Institute, Health Sciences School, University of Minho, Campus de Gualtar, 4710 057 Braga, Portugal
FASEB J 21:1126-36. 2007..This gene identification provides important clues that can help elucidate the specific biological role of ataxin-3 and unveil some of the physiological effects caused by its absence or diminished function...
- Selective occurrence of TDP-43-immunoreactive inclusions in the lower motor neurons in Machado-Joseph diseaseChun Feng Tan
Department of Pathology, Brain Research Institute, University of Niigata, 1 757 Asahimachi, Niigata, Japan
Acta Neuropathol 118:553-60. 2009..However, the immunohistochemical findings strongly suggested that in MJD, in addition to the polyglutamine-dependent disease process, TDP-43-related pathogenesis is associated with degeneration and death of the lower motor neurons...
- Consistent affection of the central somatosensory system in spinocerebellar ataxia type 2 and type 3 and its significance for clinical symptoms and rehabilitative therapyUdo Rüb
Department of Clinical Neuroanatomy, J W Goethe University, Theodor Stern Kai 7, D 60590 Frankfurt Main, Germany
Brain Res Rev 53:235-49. 2007....
- Frequency analysis of autosomal dominant cerebellar ataxias in Taiwanese patients and clinical and molecular characterization of spinocerebellar ataxia type 6W Soong B
Department of Neurology, National Yang Ming University School of Medicine, Taipei, Taiwan, Republic of China
Arch Neurol 58:1105-9. 2001..The prevalence of SCA in the ethnic Chinese on Taiwan remains unclear. Moreover, there has been no report of SCA type 6 (SCA6) among Chinese people...
- Misfolding promotes the ubiquitination of polyglutamine-expanded ataxin-3, the defective gene product in SCA3/MJDNihar Ranjan Jana
Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon 122 050, India
Neurotox Res 6:523-33. 2004....
- Clinical and molecular events in patients with Machado-Joseph disease under lamotrigine therapyC S Liu
Vascular and Genomic Research Center, Changhua Christian Hospital, Changhua, Taiwan
Acta Neurol Scand 111:385-90. 2005..Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 is an autosomal dominant spinocerebellar degeneration, for which there is no effective treatment...
- The shortest expanded allele of the MJD1 gene in a Chinese MJD kindred with autonomic dysfunctionWeihong Gu
National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
Eur Neurol 52:107-11. 2004....
- Structural and functional analysis of the Josephin domain of the polyglutamine protein ataxin-3Michelle K M Chow
Department of Biochemistry and Molecular Biology, P O Box 13D, Monash University, VIC 3800, Australia
Biochem Biophys Res Commun 322:387-94. 2004..However, its presence destabilizes the Josephin domain. The implications of these data in the pathogenesis of polyglutamine repeat proteins are discussed...
- Genetic polymorphism of MJD1 alleles and molecular analysis of SCA3 patients from Rio de Janeiro, BrazilRaquel S Gestinari
Serviço de Genética Humana, Departamento de Biologia Celular e Genetica, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Brazil
Genet Test 8:281-5. 2004..We also detected expanded alleles with 68-73 CAG repeats in 3 out of 9 ataxic patients...
- Brainstem in Machado-Joseph disease: atrophy or small size?Y Horimoto
Choju Medical Institute, Fukushimura Hospital, Yamanaka, Noyori, Toyohashi, Japan
Eur J Neurol 15:102-5. 2008..Such differences between regions in atrophy progression must be caused by a difference in the neuropathological course...
- Identification of a novel 45 repeat unstable allele associated with a disease phenotype at the MJD1/SCA3 locusQuasar Saleem Padiath
Functional Genomics Unit, Institute of Genomics and Integrative Biology Formerly Centre for Biochemical Technology, CSIR, Delhi, India
Am J Med Genet B Neuropsychiatr Genet 133:124-6. 2005We report a three generation Indian pedigree with the proband having 45 repeats at the Machado Joseph Disease (MJD)/spinocerebellar ataxia 3 (SCA3) disease locus...
- Full-length expanded ataxin-3 enhances mitochondrial-mediated cell death and decreases Bcl-2 expression in human neuroblastoma cellsHui Fang Tsai
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC
Biochem Biophys Res Commun 324:1274-82. 2004....
- Characterization of the structure and the amyloidogenic properties of the Josephin domain of the polyglutamine-containing protein ataxin-3Laura Masino
National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK
J Mol Biol 344:1021-35. 2004..Our data support a mechanism in which the thermodynamic stability of ataxin-3 is governed by the properties of the Josephin domain, but the presence of an expanded polyQ tract increases dramatically the protein's tendency to aggregate...
- Expansion of amino acid homo-sequences in proteins: insights into the role of amino acid homo-polymers and of the protein context in aggregationR P Menon
National Institute for Medical Research, London, NW7 1AA, UK
Cell Mol Life Sci 63:1677-85. 2006..The nature of the amino acid homo-sequences also has a strong influence on aggregation. From our studies, we draw general conclusions on the effect of the protein architecture and of the amino acid homo-sequence on pathology...
- Cis-acting factors promoting the CAG intergenerational instability in Machado-Joseph diseaseSandra Martins
IPATIMUP Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Portugal
Am J Med Genet B Neuropsychiatr Genet 147:439-46. 2008..In summary, our findings point to different mechanisms of instability underlying male and female meioses, as well as contraction and expansion processes in MJD...
- Effects of SCA1, MJD, and DPRLA triplet repeat polymorphisms on cognitive phenotypes in a normal population of adolescent twinsM Luciano
Queensland Institute of Medical Research, Brisbane, Australia
Am J Med Genet B Neuropsychiatr Genet 144:95-100. 2007..Given the number of statistical tests performed, it is unlikely that trinucleotide repeat variation in the normal range for these genes influences variation in normal cognition...
- Spinocerebellar ataxia type 1, 2, and 3 and restless legs syndrome: striatal dopamine D2 receptor status investigated by [11C]raclopride positron emission tomographyMatthias Reimold
Department of Nuclear Medicine, University of Tubingen, Germany
Mov Disord 21:1667-73. 2006..RLS in SCA was not accompanied by a significant reduction of D(2) receptor availability in the striatum. This missing correlation may point to an extrastriatal origin of RLS...
- p45, an ATPase subunit of the 19S proteasome, targets the polyglutamine disease protein ataxin-3 to the proteasomeHongfeng Wang
Hefei National Laboratory for Physical Sciences at Microscale and Department of Neurobiology, School of Life Sciences, University of Science and Technology of China, PR China
J Neurochem 101:1651-61. 2007..We also show that other three ATPases of the 19S proteasome, MSS1, p48, and p56 have no effect on ataxin-3 degradation. These data provide evidence that p45 plays an important role in regulating ataxin-3 degradation by the proteasome...
- Potassium channel dysfunction and depolarized resting membrane potential in a cell model of SCA3Monika Jeub
Department of Neurology, University of Bonn Medical Center, Sigmund Freud Strasse 25, D 53105 Bonn, Germany
Exp Neurol 201:182-92. 2006..These findings indicate that electrophysiological properties are altered in mutant ataxin-3 expressing neuronal cells and may contribute to neuronal dysfunction in SCA3...
- A multistep mutation mechanism drives the evolution of the CAG repeat at MJD/SCA3 locusSandra Martins
IPATIMUP Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
Eur J Hum Genet 14:932-40. 2006....
- Spinocerebellar ataxia types 2 and 3 segregating simultaneously in a single familyMarcondes C Franca
Department of Neurology, Universidade Estadual de Campinas UNICAMP, Campinas, Brazil
Mov Disord 21:1051-3. 2006..In such situations, molecular confirmation of all patients may avoid misdiagnosis of SCA subtypes and eventual errors in predictive testing of unaffected family members...
- Late-onset leanness in mice with targeted ablation of melanin concentrating hormone neuronsTamar Alon
Laboratory of Molecular Genetics, The Rockefeller University, New York, New York 10021, USA
J Neurosci 26:389-97. 2006..This has implications for the pathogenesis of acquired changes of body weight and might be considered in clinical settings characterized by substantial weight changes later in life...
- Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3Annette Haacke
Dept of Cellular Biochemistry, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany
Hum Mol Genet 15:555-68. 2006..These results establish the critical role of C-terminal, proteolytic fragments of AT3 in the molecular pathomechanism of SCA3, in strong support of the toxic fragment hypothesis...
- Mouse models of Machado-Joseph disease and other polyglutamine spinocerebellar ataxiasVeronica F Colomer Gould
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
NeuroRx 2:480-3. 2005....
- Ectoine alters subcellular localization of inclusions and reduces apoptotic cell death induced by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretchKentaro Furusho
Department of Neurology, Institute of Clinical Medicine, Graduate School of Comprehensive Medical Sciences, University of Tsukuba, Tsukuba 305 8575, Japan
Neurobiol Dis 20:170-8. 2005..Our findings suggest that ectoine, a natural osmoprotectant in bacteria, may function as a novel molecule protecting cells from polyglutamine-induced toxicity...
- Survival estimates for patients with Machado-Joseph disease (SCA3)C Kieling
Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
Clin Genet 72:543-5. 2007..Early onset and large CAG length predicted shorter overall survival times. This study presents quantitative data on the impact of MJD on overall survival, a phenomenon that is related to CAG length, age at onset, and year of birth...
- Dynamic expression of Hsp27 in the presence of mutant ataxin-3Wei Hsiu Chang
Department of Life Science, Tunghai University, Taichung, Taiwan
Biochem Biophys Res Commun 336:258-67. 2005..However, this increased Hsp27 still cannot reverse the global dysfunction of cellular proteins due to accumulation of cytotoxic effects...
- Spinocerebellar ataxia type 6 in Mainland China: molecular and clinical features in four familiesHong Jiang
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
J Neurol Sci 236:25-9. 2005..In the 4 families with SCA6, we found significant anticipation in the absence of genetic instability on transmission. This is the first report of geographic cluster of families with SCA6 subtype in Mainland China...
- Cambodian founder effect for spinocerebellar ataxia type 3 (Machado-Joseph disease)Suman Jayadev
Department of Neurology, University of Washington, USA
J Neurol Sci 250:110-3. 2006..The prevalence of the various subtypes of SCA varies worldwide from country to country. Neurologists should be alert to the possibility of SCA 3 in Cambodian patients with unexplained cerebellar ataxia...
- Sequence-dependent and independent inhibition specific for mutant ataxin-3 by small interfering RNAYi Li
Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
Ann Neurol 56:124-9. 2004..5%) by this siRNA possibly due to difference of the secondary structure of the target RNA. This is the first report of sequence-independent discrimination of mutant and wild-type alleles by siRNA...
- Chemical chaperones reduce aggregate formation and cell death caused by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretchHideaki Yoshida
Department of Neurology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, 305 8575, Japan
Neurobiol Dis 10:88-99. 2002..Our results indicate the potentially useful therapeutic strategy of the chemical chaperones in preventing cell death in MJD...
- Conserved domains and lack of evidence for polyglutamine length polymorphism in the chicken homolog of the Machado-Joseph disease gene product ataxin-3I Linhartova
Institute of Biochemistry and Molecular Cell Biology, Vienna Biocenter, University of Vienna, Dr Bohr Gasse 9, A 1030, Vienna, Austria
Biochim Biophys Acta 1444:299-305. 1999..In the first such analysis in a non-primate species we found that in contrast to primates, the chicken CAG repeat is short and genetically stable...
- Prenatal diagnosis of Machado-Joseph disease/Spinocerebellar Ataxia Type 3 in Taiwan: early detection of expanded ataxin-3Hui Fang Tsai
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, Republic of China
J Clin Lab Anal 17:195-200. 2003..Early detection of both normal and expanded ataxin-3 in fetal tissues was first demonstrated in the present study...
- Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesityJ Hara
Department of Pharmacology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki 305 8575, Japan
Neuron 30:345-54. 2001..Orexin/ataxin-3 mice provide a valuable model for studying the pathophysiology and treatment of narcolepsy...
- Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in DrosophilaJ M Warrick
Department of Biology, University of Pennsylvania and University of Pennsylvania Medical School, Philadelphia 19104, USA
Cell 93:939-49. 1998..Our results demonstrate that cellular mechanisms of human glutamine-repeat disease are conserved in invertebrates. This fly model will aid in identifying additional factors that modulate neurodegeneration...
- Molecular analyses of Machado-Joseph diseaseT Kobayashi
Graduate School of Biostudies, Kyoto University, Kyoto, and CREST, Japan Science and Technology Corporation, Japan
Cytogenet Genome Res 100:261-75. 2003
- Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70J M Warrick
Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Nat Genet 23:425-8. 1999..Our studies indicate that HSP70 or related molecular chaperones may provide a means of treating these and other neurodegenerative diseases associated with abnormal protein conformation and toxicity...
- Gene expression profiling in ataxin-3 expressing cell lines reveals distinct effects of normal and mutant ataxin-3Bernd O Evert
Department of Neurology, University of Bonn, Sigmund Freud Str 25, 53105 Bonn, Germany
J Neuropathol Exp Neurol 62:1006-18. 2003....
- Site-specific mutagenesis in a homogeneous polyglutamine tract: application to spinocerebellar ataxin-3Yu Wai Chen
Centre for Protein Engineering and Cambridge University Chemical Laboratory, MRC Centre, Hills Road, Cambridge CB2 2QH, UK
Protein Eng 16:1-4. 2003..The method reported here bypasses many problems that can arise from PCR-based mutagenesis methods...
- Intermediate CAG repeat lengths (53,54) for MJD/SCA3 are associated with an abnormal phenotypeN van Alfen
Department of Neurology, University Medical Center, Nijmegen, The Netherlands
Ann Neurol 49:805-7. 2001..Central neurological abnormalities are only present in 2. This family shows that intermediate repeat lengths can be pathogenic and may predispose for restless legs and peripheral nerve disorder...
- Destabilization of a non-pathological variant of ataxin-3 results in fibrillogenesis via a partially folded intermediate: a model for misfolding in polyglutamine diseaseMichelle K M Chow
Department of Biochemistry and Molecular Biology, Structural Biology Group, Monash University, Clayton Campus, PO Box 13D, Wellington Rd, 3800, Clayton, Vic, Australia
J Mol Biol 335:333-41. 2004..The implications of this are considered in the wider context of the development and pathogenesis of polyglutamine diseases...
- Neuronal intranuclear inclusions, dysregulation of cytokine expression and cell death in spinocerebellar ataxia type 3B O Evert
Department of Neurology, University of Bonn, Germany
Clin Neuropathol 25:272-81. 2006....
- [Mechanisms to control degradation of polyglutamine-containing protein]Kei Ichi Nakayama
Department of Molecular and Cellular Biology, Kyushu University, Fukuoka
Rinsho Shinkeigaku 43:906-8. 2003..These findings suggest that E4 is a rate-limiting factor of degradation of pathologic polyglutamine-containing proteins, and may give a potential tool for gene therapy to control the clinical conditions of MJD...
- Expression of expanded polyglutamine protein induces behavioral changes in Drosophila (polyglutamine-induced changes in Drosophila)Yun Taik Kim
Department of Life Science, Sogang University, 1 Shinsu dong, Mapo gu, Seoul 121 742, Korea
Cell Mol Neurobiol 24:109-22. 2004..The study shows that such Drosophila transgenic models express olfactory dysfunction and ataxic behavior as observed in human patients...
- Haplotype study in Dutch SCA3 and SCA6 families: evidence for common founder mutationsDineke S Verbeek
Department of Medical Genetics, University Medical Center, Stratenum, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
Eur J Hum Genet 12:441-6. 2004..These results strongly suggest that ADCA families can be traced back to common ancestors in particular parts of the Netherlands...
- Defining a metabolic phenotype in the brain of a transgenic mouse model of spinocerebellar ataxia 3J L Griffin
Department of Biochemistry, University of Cambridge, United Kingdom
Physiol Genomics 16:334-40. 2004..This study suggests high-resolution (1)H-NMR spectroscopy coupled with pattern recognition may provide a rapid method for assessing the phenotype of animal models of human disease...
- A simple method for the detection of neurologic disorders associated with CAG repeat expansion using PCR-microtiter plate hybridizationY Lee
Department of Clinical Research Center, Samsung Biomedical Research Institute, Sungkyunkwan University, Samsung Medical Center, 50 Ilwon Dong, Kangnam Ku, 135 710, Seoul, South Korea
J Biotechnol 95:215-23. 2002..Also, our design of the probe is unique in that the probe motif stem from the unrelated gene sequence and not from the synthetic oligonucleotides...
- The genomic structure and expression of MJD, the Machado-Joseph disease geneY Ichikawa
Department of Neurology, Graduate School of Medicine, The University of Tokyo, Japan
J Hum Genet 46:413-22. 2001..The sequences of these latter clones relative to the MJD gene in B445M7 indicate that there are three alternative splicing sites and eight polyadenylation signals in MJD that are used to generate the differently sized transcripts...
- A genetic model for human polyglutamine-repeat disease in Drosophila melanogasterN M Bonini
Department of Biology, University of Pennsylvania, Philadelphia 19104 6018, USA
Philos Trans R Soc Lond B Biol Sci 354:1057-60. 1999..By applying the power of Drosophila genetics to the problem of human polyglutamine-induced neural degeneration, we hope to identify ways to prevent and treat these diseases in humans...
- Pharmacological treatments of cerebellar ataxiaMasafumi Ogawa
Department of Neurology, National Center Hospital for Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
Cerebellum 3:107-11. 2004..The thyrotropin-releasing hormone, D-cycloserine, and acetazolamide for SCA6 may have some efficacy. However, a well-designed double-blind crossover trial is needed to confirm the effect...
- Frequency of SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindredsB Tang
Department of Neurology, Xiangya Hospital, Hunan Medical University, People s Republic of China
Arch Neurol 57:540-4. 2000....
- Familial pediatric rapidly progressive extrapyramidal syndrome: is it Hallervorden-Spatz disease?Ambar Chakravarty
Department of Neurology, Vivekananda Institute of Medical Sciences, Calcutta, India
Pediatr Neurol 29:170-2. 2003..The diagnosis should be considered a variant form of HSD...
- Autosomal dominant cerebellar ataxia: frequency analysis and clinical characterization of 45 families from PortugalJ Vale
Neurology Department, Hospital de Egas Moniz CHLO, Lisbon, Portugal
Eur J Neurol 17:124-8. 2010..The relative frequency of the different autosomal dominant cerebellar ataxia (ADCA) varies widely amongst different geographic locations. Here we describe a series of 45 ADCA families from Portugal...
- Multiplex families with multiple system atrophyKenju Hara
Departments of Neurology, Center for Bioresource based Researches, Brain Research Institute, Niigata University, Niigata, Japan
Arch Neurol 64:545-51. 2007..Multiple system atrophy (MSA) has been considered a sporadic disease, without patterns of inheritance...
- Brain glyceraldehyde-3-phosphate dehydrogenase activity in human trinucleotide repeat disordersS J Kish
Human Neurochemical Pathology Laboratory, Center for Addiction and Mental Health, Toronto, Ontario, Canada
Arch Neurol 55:1299-304. 1998....
- Preimplantation genetic diagnosis of spinocerebellar ataxia 3 by (CAG)(n) repeat detectionM Drusedau
Research Institute Growth and Development GROW, Academic Hospital Maastricht, Maastricht, The Netherlands
Mol Hum Reprod 10:71-5. 2004..One embryo was diagnosed as affected whereas six embryos were diagnosed as unaffected. Two unaffected embryos were transferred and resulted in a singleton pregnancy and the birth of a healthy girl...
- Trinucleotide repeats in 202 families with ataxia: a small expanded (CAG)n allele at the SCA17 locusI Silveira
UnIGENe, IBMC, Rua do Campo Alegre 823, 4150 180, Porto, Portugal
Arch Neurol 59:623-9. 2002..However, in some instances the molecular diagnosis is considered indeterminate because of the overlap between normal and affected allele ranges. In addition, the mechanism that generates expanded alleles is not completely understood...
- A prospective study of SCA3 gait ataxia described through a Markovian methodSuzi Camey
Department of Statistics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Neuroepidemiology 34:163-70. 2010..Studies on the natural history of rare, chronic diseases like spinocerebellar ataxia 3 (SCA3) are hard to be done, since patients enter the study with variable disease durations and are followed up at irregular intervals...
- CAG repeat disorder models and human neuropathology: similarities and differencesMitsunori Yamada
Department of Pathology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata, 951 8585, Japan
Acta Neuropathol 115:71-86. 2008....
- Enhanced ATPase activities as a primary defect of mutant valosin-containing proteins that cause inclusion body myopathy associated with Paget disease of bone and frontotemporal dementiaAtsushi Manno
Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies, Kyoto 606 8501, Japan
Genes Cells 15:911-22. 2010..Elevated ATPase activities, thus, may be a hidden primary defect causing IBMPFD pathological phenotypes, which would be revealed when abnormal proteins are accumulated, as typically observed in aging...
- Treatment of cerebellar ataxia with 5-HT1A agonistAsako Takei
Hokuyukai Neurology Hospital, Niju yon ken, Nishi ku, Sapporo, Japan
Cerebellum 4:211-5. 2005..Responsive patients exhibited only mild ataxia. The doses of 5-HT1A agonists that have been used successfully ranged from 12.5 mg/day to 60 mg/day (or 1 mg/kg), and were well tolerated by most patients...
- Pathology of CAG repeat diseasesM Yamada
Department of Pathology, Brain Research Institute, Niigata University, Japan
Neuropathology 20:319-25. 2000....
- Nuclear bodies and ribonucleoprotein biogenesisMichael D Hebert; Fiscal Year: 2010..Certain diseases, such as cancer and some neurodegenerative disorders, may alter Cajal body and Gem activity. ..
- Nuclear bodies and ribonucleoprotein biogenesisMICHAEL HEBERT; Fiscal Year: 2009..Certain diseases, such as cancer and some neurodegenerative disorders, may alter Cajal body and Gem activity. ..
- Mechanisms of Ataxin-1 Mediated Purkinje Cell DeathPARMINDER VIG; Fiscal Year: 2003..Further, changes observed in SCA-1 patients and in transgenic mice will be compared with that in Machado-Joseph disease/SCA-3, other cerebellar ataxias and normal controls. ..
- Mechanisms of Ataxin-1 Mediated Purkinje Cell DeathPARMINDER VIG; Fiscal Year: 2007..Further, changes observed in SCA-1 patients and in transgenic mice will be compared with that in Machado-Joseph disease/SCA-3, other cerebellar ataxias and normal controls. ..
- Mechanisms of Ataxin-1 Mediated Purkinje Cell DeathPARMINDER VIG; Fiscal Year: 2006..Further, changes observed in SCA-1 patients and in transgenic mice will be compared with that in Machado-Joseph disease/SCA-3, other cerebellar ataxias and normal controls. ..
- Structures and functions of the human Josephin domain-containing proteinsPatrick J Loll; Fiscal Year: 2010....
- Structures and functions of the human Josephin domain-containing proteinsPATRICK LOLL; Fiscal Year: 2009....
- Triplet Repeat Disease:Requirement for Caspase CleavageLisa Ellerby; Fiscal Year: 2007..abstract_text> ..
- TRIPLET REPEAT DISEASE: REQUIREMENT FOR CASPASE CLEAVAGELisa Ellerby; Fiscal Year: 2001..We will test our hypothesis that the seven polyglutamine containing proteins are pro-apoptotic, and that the pro-apoptotic phenotype is dependent upon cleavage of these proteins by cell death executioners, the caspases. ..
- Crystallization of Ataxin-3PATRICK LOLL; Fiscal Year: 2005..The molecular understanding of ataxin-3 that will be obtained from this work is a prerequisite for any rational design of therapeutics that will interfere with the protein's aberrant folding and aggregation. ..
- Mechanisms of Polyglutamine NeurodegenerationHenry Paulson; Fiscal Year: 2009..They may also shed light on the role of protein quality control, and particularly of de-ubiquitinating enzymes, in age-related neurodegenerative diseases characterized by protein misfolding and aggregation. ..
- MECHANISMS OF GLUTAMINE REPEAT NEURODEGENERATIONHenry Paulson; Fiscal Year: 2004..abstract_text> ..
- Mouse Model and Interactors for Machado-Joseph DiseaseVeronica Colomer; Fiscal Year: 2004DESCRIPTION (Adapted from applicant's abstract): Machado Joseph disease (MJD), or spinocerebellar ataxia-3 (SCA-3), is the most common dominant spinocerebellar ataxia...
- Structure-function of inositol trisphosphate receptorIlya Bezprozvanny; Fiscal Year: 2009..Dopamine-induced responses in striatal medium spiny neurons will be studied by Ca2+ imaging. Experiments with striatal neurons from DARPP-32 and D2 receptor knockout mice will be performed. ..
- INTERACTIONS OF CALCIUM CHANNELS WITH ADAPTOR PROTEINSIlya Bezprozvanny; Fiscal Year: 2003....
- Screen:Blockers of a CaV2.2-Mint-PDZ1 association (RMI)Ilya Bezprozvanny; Fiscal Year: 2004..Biological activity of compounds identified in the full HTS screen will be tested in whole animal pain assays (formalin, hot plate, tail flick). ..
- THE GENETICS OF IDIOPATHIC BASAL GANGLIA CALCIFICATIONDaniel Geschwind; Fiscal Year: 2004..Physical mapping and candidate screening for mutations will be pursued as the region is narrowed to identify the IBGC gene. A genome scan will be performed in families who are not linked to the chr.14 locus. ..
- Metabolomics and metabolic compartmentation in the brainJulian Griffin; Fiscal Year: 2006..To correlate NMR observable metabolite changes with transcriptional changes. Our data will provide proof-of principle for this methodology, and establish a means for exploring other neurolodegenerative disorders. ..
- Regulation of the SCA3 Disease Gene and Its ProteinSARAH BERKE; Fiscal Year: 2003..The studies proposed here will further our understanding of ataxin-3 production and degradation, perhaps leading to the development of therapies for these currently untreatable diseases. ..
- Mechanisms of Polyglutamine NeurodegenerationHenry L Paulson; Fiscal Year: 2010..This grant will explore the basis of SCA3 in order that we can ultimately develop therapies for this fatal disease based on a better understanding of disease mechanisms. ..
- Iron in the pathogenesis of Friedreich's ataxiaARNULF HANS WERNER KOEPPEN; Fiscal Year: 2010..Chelation therapy in an effort to remove iron from affected tissues remains controversial. The proposed investigation will help clarify the potential benefit of chelation therapy in FRDA. ..
- Integrating Quality Control: Studies of CHIP in Age-related NeurodegenerationHenry L Paulson; Fiscal Year: 2010..Understanding this machinery may suggest routes to therapy for a large range of sporadic and hereditary neurodegenerative diseases that occur as we age. ..
- Integrating Quality Control: Studies of CHIP in Age-related NeurodegenerationHenry Paulson; Fiscal Year: 2009..Understanding this machinery may suggest routes to therapy for a large range of sporadic and hereditary neurodegenerative diseases that occur as we age. ..
- A Comprehensive Approach to Identification of Autism Susceptibility GenesDaniel H Geschwind; Fiscal Year: 2010..All phenotypic and genotype data will be made accessible via the Internet on a rolling basis, including minority families, further enhancing the value of this resource to the community. ..
- Genomewide Search--Autism Susceptibility Loci-supplementDaniel Geschwind; Fiscal Year: 2003..This work is a direct response to Title 1 of the Pediatric Health Act of 2000 which authorizes and mandates an increased NIH commitment to autism gene banking. ..
- Identification of targets of FoxP2 in the brainDaniel Geschwind; Fiscal Year: 2006..This proposal has a strong screening component in an area where no molecular mechanisms have been identified and fits well within the R21 framework. ..
- Mechanisms of Polyglutamine NeurodegenerationHenry Paulson; Fiscal Year: 2007..They may also shed light on the role of protein quality control, and particularly of de-ubiquitinating enzymes, in age-related neurodegenerative diseases characterized by protein misfolding and aggregation. ..
- Analysis of Fbx2 Family of Ubiquitin LigasesHenry Paulson; Fiscal Year: 2007..The results may also have implications for the pathogenesis of two poorly understood neurological diseases, DYT1 dystonia and familial neuroserpin dementia. ..
- ASYMMETRICALLY EXPRESSED GENES IN DEVELOPING CEREBRUMDaniel Geschwind; Fiscal Year: 2003..abstract_text> ..
- Identification and Characterization of Asymmetrically-Expressed GenesDaniel Geschwind; Fiscal Year: 2007..All of this will clearly inform the study of human neurodevelopmental disorders that are related to speech and language, as well as probe the utility and limitations of animal models for these disorders. ..
- Novel Genetic Risk Factors for Alzheimer's Disease (AD) & Frontotemporal DementiaDaniel Geschwind; Fiscal Year: 2009..abstract_text> ..
- Tissue Transglutaminase in Neurologic InjuryTHUNG SHEN LAI; Fiscal Year: 2007..The inhibitors will be used to investigate the role of TTG in the pathogenesis of expanded polyQ diseases. Current proposal will lead to new therapy for HD and other neurologic disorders. ..
- Novel Genetic Risk Factors for Alzheimer's Disease (AD) & Frontotemporal DementiaDaniel Geschwind; Fiscal Year: 2007..abstract_text> ..
- A Genomewide Search for Autism Susceptibilty LociDaniel Geschwind; Fiscal Year: 2006..All phenotypic and genotype data will be made accessible via the Internet on a rolling basis, further enhancing the value of this resource to the community. ..
- Training Grant in Neurobehavioral GeneticsDaniel Geschwind; Fiscal Year: 2007....