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Polyglutamine-expanded ataxin-3 causes cerebellar dysfunction of SCA3 transgenic mice by inducing transcriptional dysregulation.

In the present study, we prepared a SCA3 animal model by generating transgenic mice expressing polyglutamine-expanded ataxin-3-Q79. Ataxin-3-Q79 was expressed in brain areas implicated in SCA3 neurodegeneration, including cerebellum, pontine nucleus and substantia nigra. Ataxin-3-Q79 transgenic mice displayed motor dysfunction with an onset age of 5-6 months, and neurological symptoms deteriorated in the following months. A prominent neuronal loss was not found in the cerebellum of 10 to 11-month-old ataxin-3-Q79 mice displaying pronounced ataxic symptoms, suggesting that instead of neuronal demise, ataxin-3-Q79 causes neuronal dysfunction of the cerebellum and resulting ataxia. To test the involvement of transcriptional dysregulation in ataxin-3-Q79-induced cerebellar malfunction, microarray analysis and real-time RT-PCR assays were performed to identify altered cerebellar mRNA expressions of ataxin-3-Q79 mice. Compared to non-transgenic mice or mice expressing wild-type ataxin-3-Q22, 10 to 11-month-old ataxin-3-Q79 mice exhibited downregulated mRNA expressions of proteins involved in glutamatergic neurotransmission, intracellular calcium signaling/mobilization or MAP kinase pathways, GABA(A/B) receptor subunits, heat shock proteins and transcription factor regulating neuronal survival and differentiation. Upregulated expressions of Bax, cyclin D1 and CDK5-p39, which may mediate neuronal death, were also observed in ataxin-3-Q79 transgenic mice. The involvement of transcriptional abnormality in initiating the pathological process of SCA3 was indicated by the finding that 4 to 5-month-old ataxin-3-Q79 mice, which did not display neurological phenotype, exhibited downregulated mRNA levels of genes involved in glutamatergic signaling and signal transduction. Our study suggests that polyglutamine-expanded ataxin-3 causes cerebellar dysfunction and ataxia by disrupting the normal pattern of gene transcriptions.

Pubmed ID: 18502140


  • Chou AH
  • Yeh TH
  • Ouyang P
  • Chen YL
  • Chen SY
  • Wang HL


Neurobiology of disease

Publication Data

July 23, 2008

Associated Grants


Mesh Terms

  • Animals
  • Blotting, Southern
  • Blotting, Western
  • Cerebellum
  • Disease Models, Animal
  • Gene Expression
  • Humans
  • Immunohistochemistry
  • Machado-Joseph Disease
  • Mice
  • Mice, Transgenic
  • Nuclear Proteins
  • Oligonucleotide Array Sequence Analysis
  • Peptides
  • RNA, Messenger
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors
  • Transcription, Genetic
  • Trinucleotide Repeat Expansion