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)

Top Publications

  1. Soong B W, Lu Y C, Choo K B, Lee H Y. Frequency analysis of autosomal dominant cerebellar ataxias in Taiwanese patients and clinical and molecular characterization of spinocerebellar ataxia type 6. Arch Neurol. 2001;58:1105-9 pubmed
    ..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...
  2. Haacke A, Hartl F, Breuer P. Calpain inhibition is sufficient to suppress aggregation of polyglutamine-expanded ataxin-3. J Biol Chem. 2007;282:18851-6 pubmed
    ..These findings suggest a critical role of calpains in the pathogenesis of Spinocerebellar ataxia type 3...
  3. Rüb U, de Vos R, Brunt E, Sebesteny T, Schols L, Auburger G, et al. Spinocerebellar ataxia type 3 (SCA3): thalamic neurodegeneration occurs independently from thalamic ataxin-3 immunopositive neuronal intranuclear inclusions. Brain Pathol. 2006;16:218-27 pubmed
    ..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...
  4. Doss Pepe E, Stenroos E, Johnson W, Madura K. 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 proteolysis. Mol Cell Biol. 2003;23:6469-83 pubmed
  5. Scheel H, Tomiuk S, Hofmann K. Elucidation of ataxin-3 and ataxin-7 function by integrative bioinformatics. Hum Mol Genet. 2003;12:2845-52 pubmed
    ..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 ..
  6. Miller V, Xia H, Marrs G, Gouvion C, Lee G, Davidson B, et al. Allele-specific silencing of dominant disease genes. Proc Natl Acad Sci U S A. 2003;100:7195-200 pubmed
    ..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...
  7. Lai T, Liu Y, Tucker T, Daniel K, Sane D, Toone E, et al. Identification of chemical inhibitors to human tissue transglutaminase by screening existing drug libraries. Chem Biol. 2008;15:969-78 pubmed publisher
    ..The TGM2 inhibitors we discovered may serve as valuable lead compounds for the development of orally active TGM2 inhibitors to treat human diseases...
  8. Berke S, Schmied F, Brunt E, Ellerby L, Paulson H. Caspase-mediated proteolysis of the polyglutamine disease protein ataxin-3. J Neurochem. 2004;89:908-18 pubmed
    ..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...
  9. Bauer P, Zumrova A, Matoska V, Marikova T, Krilova S, Boday A, et al. Absence of spinocerebellar ataxia type 3/Machado-Joseph disease within ataxic patients in the Czech population. Eur J Neurol. 2005;12:851-7 pubmed
    ..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...

More Information


  1. Mittal U, Srivastava A, Jain S, Jain S, Mukerji M. Founder haplotype for Machado-Joseph disease in the Indian population: novel insights from history and polymorphism studies. Arch Neurol. 2005;62:637-40 pubmed
    ..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...
  2. Burnett B, Pittman R. The polyglutamine neurodegenerative protein ataxin 3 regulates aggresome formation. Proc Natl Acad Sci U S A. 2005;102:4330-5 pubmed
    ..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...
  3. Seidel K, Brunt E, de Vos R, Dijk F, van der Want H, Rüb U, et al. The p62 antibody reveals various cytoplasmic protein aggregates in spinocerebellar ataxia type 6. Clin Neuropathol. 2009;28:344-9 pubmed
  4. Paulson H, Das S, Crino P, Perez M, Patel S, Gotsdiner D, et al. Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain. Ann Neurol. 1997;41:453-62 pubmed
    ..The restricted expression of ataxin-3 in certain regions, however, may influence the pattern of neurodegeneration and provide clues to the protein's function...
  5. Ikeda H, Yamaguchi M, Sugai S, Aze Y, Narumiya S, Kakizuka A. Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nat Genet. 1996;13:196-202 pubmed
    ..Our results demonstrate the potential involvement of the expanded polyglutamine as the common aetiological agent for inherited neurodegenerative diseases with CAG expansions...
  6. Matsumura R, Futamura N, Ando N, Ueno S. Frequency of spinocerebellar ataxia mutations in the Kinki district of Japan. Acta Neurol Scand. 2003;107:38-41 pubmed
    ..To determine the frequencies of spinocerebellar ataxias (SCAs) in the Kinki district, the western part of the main island of Japan...
  7. Rüb U, Gierga K, Brunt E, de Vos R, Bauer M, Schols L, et al. Spinocerebellar ataxias types 2 and 3: degeneration of the pre-cerebellar nuclei isolates the three phylogenetically defined regions of the cerebellum. J Neural Transm (Vienna). 2005;112:1523-45 pubmed
  8. Jiang M, Jin C, Lin C, Qiu G, Liu Z, Wang C, et al. [Analysis and application of SCA1 and SCA3/MJD gene CAG repeats in Han population in Northeastern China]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2004;21:83-5 pubmed
  9. Jung J, Bonini N. CREB-binding protein modulates repeat instability in a Drosophila model for polyQ disease. Science. 2007;315:1857-9 pubmed
    ..Pharmacological treatment to normalize acetylation suppressed instability. Thus, toxic consequences of pathogenic polyQ protein may include enhancing repeat instability...
  10. Maciel P, Costa M, Ferro A, Rousseau M, Santos C, Gaspar C, et al. Improvement in the molecular diagnosis of Machado-Joseph disease. Arch Neurol. 2001;58:1821-7 pubmed
    ..Direct detection of the gene mutation allows for the confirmation of the clinical diagnosis of Machado-Joseph disease (MJD), the most frequent cause of autosomal dominant spinocerebellar ataxia worldwide...
  11. Schols L, Vieira Saecker A, Schols S, Przuntek H, Epplen J, Riess O. Trinucleotide expansion within the MJD1 gene presents clinically as spinocerebellar ataxia and occurs most frequently in German SCA patients. Hum Mol Genet. 1995;4:1001-5 pubmed
    ..These results demonstrate that the MJD mutation causes the disease phenotype of most SCA patients in Germany...
  12. Tan C, Yamada M, Toyoshima Y, Yokoseki A, Miki Y, Hoshi Y, et al. Selective occurrence of TDP-43-immunoreactive inclusions in the lower motor neurons in Machado-Joseph disease. Acta Neuropathol. 2009;118:553-60 pubmed publisher
    ..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...
  13. Maciel P, Gaspar C, Guimaraes L, Goto J, Lopes Cendes I, Hayes S, et al. Study of three intragenic polymorphisms in the Machado-Joseph disease gene (MJD1) in relation to genetic instability of the (CAG)n tract. Eur J Hum Genet. 1999;7:147-56 pubmed
  14. Martins S, Calafell F, Gaspar C, Wong V, Silveira I, Nicholson G, et al. Asian origin for the worldwide-spread mutational event in Machado-Joseph disease. Arch Neurol. 2007;64:1502-8 pubmed
    ..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...
  15. Rüb U, Brunt E, Deller T. New insights into the pathoanatomy of spinocerebellar ataxia type 3 (Machado-Joseph disease). Curr Opin Neurol. 2008;21:111-6 pubmed publisher
    ..This review summarizes recent neuropathological findings in spinocerebellar ataxia type 3 and discusses their relevance for clinical neurology...
  16. Carvalho D, La Rocque Ferreira A, Rizzo I, Imamura E, Speck Martins C. Homozygosity enhances severity in spinocerebellar ataxia type 3. Pediatr Neurol. 2008;38:296-9 pubmed publisher
    ..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...
  17. Alves S, Nascimento Ferreira I, Auregan G, Hassig R, Dufour N, Brouillet E, et al. Allele-specific RNA silencing of mutant ataxin-3 mediates neuroprotection in a rat model of Machado-Joseph disease. PLoS ONE. 2008;3:e3341 pubmed publisher
    ..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...
  18. Chattopadhyay B, Basu P, Gangopadhyay P, Mukherjee S, Sinha K, Chakraborty A, et al. Variation of CAG repeats and two intragenic polymorphisms at SCA3 locus among Machado-Joseph disease/SCA3 patients and diverse normal populations from eastern India. Acta Neurol Scand. 2003;108:407-14 pubmed
    ..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...
  19. Perez M, Paulson H, Pendse S, Saionz S, Bonini N, Pittman R. Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J Cell Biol. 1998;143:1457-70 pubmed
    ..In addition, we demonstrate that the nuclear environment may be critical for seeding polyglutamine aggregates...
  20. Hayashi M, Kobayashi K, Furuta H. Immunohistochemical study of neuronal intranuclear and cytoplasmic inclusions in Machado-Joseph disease. Psychiatry Clin Neurosci. 2003;57:205-13 pubmed
    ..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...
  21. Rüb U, Brunt E, Del Turco D, de Vos R, Gierga K, Paulson H, et al. 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 patient. Neuropathol Appl Neurobiol. 2003;29:1-13 pubmed
  22. Pozzi C, Valtorta M, Tedeschi G, Galbusera E, Pastori V, Bigi A, et al. Study of subcellular localization and proteolysis of ataxin-3. Neurobiol Dis. 2008;30:190-200 pubmed publisher
    ..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...
  23. Lima M, Costa M, Montiel R, Ferro A, Santos C, Silva C, et al. Population genetics of wild-type CAG repeats in the Machado-Joseph disease gene in Portugal. Hum Hered. 2005;60:156-63 pubmed
  24. Rüb U, Seidel K, Ozerden I, Gierga K, Brunt E, Schols L, et al. Consistent affection of the central somatosensory system in spinocerebellar ataxia type 2 and type 3 and its significance for clinical symptoms and rehabilitative therapy. Brain Res Rev. 2007;53:235-49 pubmed
  25. Rodrigues A, Coppola G, Santos C, Costa M, Ailion M, Sequeiros J, et al. Functional genomics and biochemical characterization of the C. elegans orthologue of the Machado-Joseph disease protein ataxin-3. FASEB J. 2007;21:1126-36 pubmed
    ..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...
  26. Bichelmeier U, Schmidt T, Hübener J, Boy J, Ruttiger L, Häbig K, et al. Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidence. J Neurosci. 2007;27:7418-28 pubmed
    ..These studies indicate that nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3 in vivo...
  27. Paulson H. Dominantly inherited ataxias: lessons learned from Machado-Joseph disease/spinocerebellar ataxia type 3. Semin Neurol. 2007;27:133-42 pubmed
    ..Also discussed are current and future therapeutic opportunities for MJD/SCA3 in particular, many of which have relevance to other SCAs...
  28. Warrick J, Morabito L, Bilen J, Gordesky Gold B, Faust L, Paulson H, et al. Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism. Mol Cell. 2005;18:37-48 pubmed
    ..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...
  29. Colomer Gould V, Goti D, Pearce D, Gonzalez G, Gao H, Bermudez de Leon M, et al. 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 mice. Neurobiol Dis. 2007;27:362-9 pubmed
    ..Our results support the toxic fragment hypothesis and narrow the mutant ataxin-3 cleavage site to the N-terminus of amino acid 190...
  30. Tort A, Portela L, Rockenbach I, Monte T, Pereira M, Souza D, et al. S100B and NSE serum concentrations in Machado Joseph disease. Clin Chim Acta. 2005;351:143-8 pubmed
    ..We evaluated the potential use of S100B and NSE serum concentrations as peripheral markers of symptomatic patients with Machado Joseph disease (MJD).
  31. Todi S, Winborn B, Scaglione K, Blount J, Travis S, Paulson H. Ubiquitination directly enhances activity of the deubiquitinating enzyme ataxin-3. EMBO J. 2009;28:372-82 pubmed publisher
    ..Ataxin-3 is the first reported DUB in which ubiquitination directly regulates catalytic activity. We propose a new function for protein ubiquitination in regulating the activity of certain DUBs and perhaps other enzymes...
  32. Goti D, Katzen S, Mez J, Kurtis N, Kiluk J, Ben Haïem L, et al. A mutant ataxin-3 putative-cleavage fragment in brains of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentration. J Neurosci. 2004;24:10266-79 pubmed
  33. Rüb U, Brunt E, de Vos R, Del Turco D, Del Tredici K, Gierga K, et al. Degeneration of the central vestibular system in spinocerebellar ataxia type 3 (SCA3) patients and its possible clinical significance. Neuropathol Appl Neurobiol. 2004;30:402-14 pubmed
    ..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...
  34. Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet. 1994;8:221-8 pubmed
    ..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...
  35. Yamada M, Hayashi S, Tsuji S, Takahashi H. Involvement of the cerebral cortex and autonomic ganglia in Machado-Joseph disease. Acta Neuropathol. 2001;101:140-4 pubmed
    ..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...
  36. Gwinn Hardy K, Singleton A, Ó Súilleabháin P, Boss M, Nicholl D, Adam A, et al. Spinocerebellar ataxia type 3 phenotypically resembling parkinson disease in a black family. Arch Neurol. 2001;58:296-9 pubmed
    ..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...
  37. Martins S, Calafell F, Wong V, Sequeiros J, Amorim A. A multistep mutation mechanism drives the evolution of the CAG repeat at MJD/SCA3 locus. Eur J Hum Genet. 2006;14:932-40 pubmed
  38. Tzvetkov N, Breuer P. Josephin domain-containing proteins from a variety of species are active de-ubiquitination enzymes. Biol Chem. 2007;388:973-8 pubmed
    ..These results establish JD-containing proteins as a novel family of active de-ubiquitination enzymes with wide phylogenic distribution. ..
  39. Boy J, Schmidt T, Schumann U, Grasshoff U, Unser S, Holzmann C, et al. A transgenic mouse model of spinocerebellar ataxia type 3 resembling late disease onset and gender-specific instability of CAG repeats. Neurobiol Dis. 2010;37:284-93 pubmed publisher
    ..Few and small intranuclear aggregates appeared first at the age of 18 months, further supporting the claim that neuronal dysfunction precedes the formation of intranuclear aggregates...
  40. Uchihara T, Iwabuchi K, Funata N, Yagishita S. Attenuated nuclear shrinkage in neurons with nuclear aggregates--a morphometric study on pontine neurons of Machado-Joseph disease brains. Exp Neurol. 2002;178:124-8 pubmed
    ..NAs of MJD are presumably linked to a mechanism that attenuates rather than accelerates nuclear shrinkage and deformity. This finding leads us to consider that NAs are not necessarily toxic to neurons in diseased human brains. ..
  41. Antony P, Mäntele S, Mollenkopf P, Boy J, Kehlenbach R, Riess O, et al. Identification and functional dissection of localization signals within ataxin-3. Neurobiol Dis. 2009;36:280-92 pubmed publisher
    ..Our findings stress the importance of investigating the mechanisms, which influence the intracellular distribution of ataxin-3 during the pathogenesis of SCA3. ..
  42. Lopes Cendes I, Teive H, Calcagnotto M, da Costa J, Cardoso F, Viana E, et al. Frequency of the different mutations causing spinocerebellar ataxia (SCA1, SCA2, MJD/SCA3 and DRPLA) in a large group of Brazilian patients. Arq Neuropsiquiatr. 1997;55:519-29 pubmed
    ..These results suggest that SCA may be occasionally caused by the SCA1 and SCA2 mutations in the Brazilian population, and that the MJD/SCA3 mutation is the most common cause of dominantly inherited SCA in Brazil. ..
  43. Lima M, Smith M, Silva C, Abade A, Mayer F, Coutinho P. Natural selection at the MJD locus: phenotypic diversity, survival and fertility among Machado-Joseph Disease patients from the Azores. J Biosoc Sci. 2001;33:361-73 pubmed
    ..The fertility component of selection is mediated by nuptiality rather than marital fertility. ..
  44. Kobayashi T, Kakizuka A. Molecular analyses of Machado-Joseph disease. Cytogenet Genome Res. 2003;100:261-75 pubmed
  45. Soong B, Liu R. Positron emission tomography in asymptomatic gene carriers of Machado-Joseph disease. J Neurol Neurosurg Psychiatry. 1998;64:499-504 pubmed
    ..7% specificity). Subclinical changes of FDG consumption, as measured by noninvasive PET, can act as an objective marker of preclinical disease activity in Machado-Joseph disease. ..
  46. Cong S, Pepers B, Evert B, Rubinsztein D, Roos R, van Ommen G, et al. Mutant huntingtin represses CBP, but not p300, by binding and protein degradation. Mol Cell Neurosci. 2005;30:560-71 pubmed
    ..In addition to the reduction of CBP, also the altered ratio of these closely related histone acetyl transferases may affect chromatin structure and transcription and thus contribute to neurodegeneration. ..
  47. Saute J, Rieder C, Castilhos R, Monte T, Schumacher Schuh A, Donis K, et al. Planning future clinical trials in Machado Joseph disease: Lessons from a phase 2 trial. J Neurol Sci. 2015;358:72-6 pubmed publisher
    In a recent phase 2 clinical trial in spinocerebellar ataxia type 3/Machado Joseph disease (SCA3/MJD), a neurogenetic disorder without specific therapy, benefits of lithium carbonate were found only on secondary efficacy outcomes, all ..
  48. Ishikawa A, Yamada M, Makino K, Aida I, Idezuka J, Ikeuchi T, et al. Dementia and delirium in 4 patients with Machado-Joseph disease. Arch Neurol. 2002;59:1804-8 pubmed
    ..Symptoms of dementia and delirium in patients with MJD could occur in the late stages, and they might be caused not by loss of cerebrocortical neurons, but by their dysfunction. ..
  49. Ghisolfi E, Maegawa G, Becker J, Zanardo A, Strimitzer I, Prokopiuk A, et al. Impaired P50 sensory gating in Machado-Joseph disease. Clin Neurophysiol. 2004;115:2231-5 pubmed
    ..These results point out the P50 paradigm as a potential tool for further neurophysiological surveying in MJD. ..
  50. Yamada M, Sato T, Shimohata T, Hayashi S, Igarashi S, Tsuji S, et al. Interaction between neuronal intranuclear inclusions and promyelocytic leukemia protein nuclear and coiled bodies in CAG repeat diseases. Am J Pathol. 2001;159:1785-95 pubmed
    ..The results suggest that the interaction between NIIs and nuclear bodies may play a role in the pathogenesis of CAG repeat diseases. ..
  51. Rüb U, de Vos R, Schultz C, Brunt E, Paulson H, Braak H. Spinocerebellar ataxia type 3 (Machado-Joseph disease): severe destruction of the lateral reticular nucleus. Brain. 2002;125:2115-24 pubmed
    ..In view of its afferent and efferent connections, destruction of the LRT probably contributes to gait ataxia in individuals suffering from SCA3. ..
  52. Cemal C, Huxley C, Chamberlain S. Insertion of expanded CAG trinucleotide repeat motifs into a yeast artificial chromosome containing the human Machado-Joseph disease gene. Gene. 1999;236:53-61 pubmed
    ..The availability of these clones for modelling of the disease in transgenic animals should allow elucidation of the role of repeat length in the phenotypic spectrum of the disease. ..
  53. Prestes P, Saraiva Pereira M, Silveira I, Sequeiros J, Jardim L. Machado-Joseph disease enhances genetic fitness: a comparison between affected and unaffected women and between MJD and the general population. Ann Hum Genet. 2008;72:57-64 pubmed
    ..07, respectively). Among affected women those who did not have children had larger CAG tracts than those who had children (p < 0.05). MJD enhances the fitness of its carriers, and this phenomenon seems to have a biological basis. ..
  54. Abele M, Burk K, Laccone F, Dichgans J, Klockgether T. Restless legs syndrome in spinocerebellar ataxia types 1, 2, and 3. J Neurol. 2001;248:311-4 pubmed
    ..The probability of developing RLS is related principally to the period over which the CAG repeat mutation exerts its effect and not to CAG repeat length or age of ataxia onset. ..
  55. Chow M, Mackay J, Whisstock J, Scanlon M, Bottomley S. Structural and functional analysis of the Josephin domain of the polyglutamine protein ataxin-3. Biochem Biophys Res Commun. 2004;322:387-94 pubmed
    ..However, its presence destabilizes the Josephin domain. The implications of these data in the pathogenesis of polyglutamine repeat proteins are discussed. ..
  56. Evert B, Schelhaas J, Fleischer H, de Vos R, Brunt E, Stenzel W, et al. Neuronal intranuclear inclusions, dysregulation of cytokine expression and cell death in spinocerebellar ataxia type 3. Clin Neuropathol. 2006;25:272-81 pubmed
    ..Our data suggest that the selectively affected neuronal populations in SCA3 undergo a complex alteration of gene expression independent from the formation of NI. ..
  57. Takei A, Honma S, Kawashima A, Yabe I, Fukazawa T, Hamada K, et al. Beneficial effects of tandospirone on ataxia of a patient with Machado-Joseph disease. Psychiatry Clin Neurosci. 2002;56:181-5 pubmed
    ..In addition, his leg pain, insomnia, anorexia, and depression, which are thought to be related to 5-HT1A receptors, were also remarkably alleviated by treatment with tandospirone. ..
  58. Yen T, Tzen K, Chen M, Chou Y, Chen R, Chen C, et al. Dopamine transporter concentration is reduced in asymptomatic Machado-Joseph disease gene carriers. J Nucl Med. 2002;43:153-9 pubmed
    ..Significantly, the results suggest that this impairment of presynaptic dopamine function actually occurs at an early stage, which was previously unrecognized in these aMJD gene carriers. ..
  59. Schmidt T, Lindenberg K, Krebs A, Schols L, Laccone F, Herms J, et al. Protein surveillance machinery in brains with spinocerebellar ataxia type 3: redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions. Ann Neurol. 2002;51:302-10 pubmed
    ..The dissociation between regulatory subunits and the proteolytic core and the changes in subcellular subunit distribution suggest perturbations of the proteosomal machinery in spinocerebellar ataxia type 3 brains. ..
  60. Gan S, Shi S, Wu J, Wang N, Zhao G, Weng S, et al. High frequency of Machado-Joseph disease identified in southeastern Chinese kindreds with spinocerebellar ataxia. BMC Med Genet. 2010;11:47 pubmed publisher
  61. Jeub M, Herbst M, Spauschus A, Fleischer H, Klockgether T, Wuellner U, et al. Potassium channel dysfunction and depolarized resting membrane potential in a cell model of SCA3. Exp Neurol. 2006;201:182-92 pubmed
    ..These findings indicate that electrophysiological properties are altered in mutant ataxin-3 expressing neuronal cells and may contribute to neuronal dysfunction in SCA3. ..
  62. Berciano J, Infante J, Garcia A, De Pablos C, Amer G, Polo J, et al. Stiff man-like syndrome and generalized myokymia in spinocerebellar ataxia type 3. Mov Disord. 2006;21:1031-5 pubmed
    ..We conclude that an excess of motor unit activity including stiff man-like syndrome and widespread myokymia may be an integral part of the SCA3 clinical spectrum...
  63. Lu M, Shih H, Huang K, Ziemann U, Tsai C, Chang F, et al. Movement-related cortical potentials in patients with Machado-Joseph disease. Clin Neurophysiol. 2008;119:1010-9 pubmed publisher
    ..Abnormalities of pre- and post-movement MRCP components provide researchers with pathophysiological insight into voluntary motor dysfunction in MJD. ..
  64. Ito N, Kamiguchi K, Nakanishi K, Sokolovskya A, Hirohashi Y, Tamura Y, et al. A novel nuclear DnaJ protein, DNAJC8, can suppress the formation of spinocerebellar ataxia 3 polyglutamine aggregation in a J-domain independent manner. Biochem Biophys Res Commun. 2016;474:626-633 pubmed publisher
  65. Lee Y, Oh M, Kim C, Hwang H, Kim J, Song S, et al. A simple method for the detection of neurologic disorders associated with CAG repeat expansion using PCR-microtiter plate hybridization. J Biotechnol. 2002;95:215-23 pubmed
    ..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. ..
  66. Zhou Y, Jiang H, Tang J, Tang B. [The advances in research on phosphorylation of polyglutamine disease]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2008;25:414-7 pubmed
  67. Shirai W, Ito S, Hattori T. Linear T2 hyperintensity along the medial margin of the globus pallidus in patients with Machado-Joseph disease and Parkinson disease, and in healthy subjects. AJNR Am J Neuroradiol. 2007;28:1993-5 pubmed
    ..Linear hyperintensity along the globus pallidus is frequently found in patients with MJD, but it can be also found in patients with PD and in control subjects, probably because of the normal aging process. ..
  68. Hayashi T, Nakajima T, Fukuhara N. [Analysis of regional cerebral blood flow and distribution volume in Machado-Joseph disease by iodine-123I IMP single photon emission computed tomography]. Rinsho Shinkeigaku. 2001;41:574-81 pubmed
    ..Our study shows that SPECT measurement of rCBF and Vd is useful for understanding the pathophysiology of MJD...
  69. Jardim L, Pereira M, Silveira I, Ferro A, Sequeiros J, Giugliani R. Neurologic findings in Machado-Joseph disease: relation with disease duration, subtypes, and (CAG)n. Arch Neurol. 2001;58:899-904 pubmed
    ..1, is a heterogeneous disorder for clinical manifestations. The reasons for the wide range of neurologic findings in this disease are poorly understood...
  70. Freeman W, Wszolek Z. Botulinum toxin type A for treatment of spasticity in spinocerebellar ataxia type 3 (Machado-Joseph disease). Mov Disord. 2005;20:644 pubmed
  71. Sharkey L, Cheng X, Drews V, Buchner D, Jones J, Justice M, et al. The ataxia3 mutation in the N-terminal cytoplasmic domain of sodium channel Na(v)1.6 disrupts intracellular trafficking. J Neurosci. 2009;29:2733-41 pubmed publisher
    ..The data demonstrate that the cytoplasmic N-terminal domain of the sodium channel is required for anterograde transport from the Golgi complex to the plasma membrane...
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    ..The patient with MJD might have a tendency to develop encephalopathy by fleroxacin, because the GABA-ergic nervous system could be involved in MJD...
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    ..919 (P=0.05), df=9]. The observed distribution peak of normal MJD1 alleles corresponding to peptides containing 10, 15, 20, and 24 glutamine suggests that stretches of 5 and 10 glutamine might constitute a functional domain of human MJD1...
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    ..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...
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    ..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...
  77. Wang G, Sawai N, Kotliarova S, Kanazawa I, Nukina N. Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B. Hum Mol Genet. 2000;9:1795-803 pubmed
    ..These results suggest that this interaction is associated with the normal function of ataxin-3 and that some functional abnormality of the HHR23 proteins might exist in MJD...
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    ..In this review, we discuss the role(s) that heat shock protein 27 (HSP27) may play in the cell death process of spinocerebellar ataxia type 3...
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    ..The presence of neuronal intranuclear inclusions (NIIs) and neuronal mosaicism has been described in some autosomal dominant spinocerebellar ataxias (SCA), but their implication in neurodegenerative mechanisms still remains unclear...
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    ..SCA 3 should be considered a differential diagnosis in adult patients who present with DRD phenotype and with a positive family history...
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    ..In summary, our findings point to different mechanisms of instability underlying male and female meioses, as well as contraction and expansion processes in MJD...
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