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

An Hsun Chou, Tu Hsueh Yeh, Pin Ouyang, Ying Ling Chen, Si Ying Chen, Hung Li Wang

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

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, GABAA/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.

Original languageEnglish
Pages (from-to)89-101
Number of pages13
JournalNeurobiology of Disease
Volume31
Issue number1
DOIs
Publication statusPublished - Jul 2008
Externally publishedYes

Keywords

  • Ataxin-3
  • Cerebellum
  • Microarray analysis
  • Polyglutamine-expanded ataxin-3
  • SCA3 transgenic mice
  • Spinocerebellar ataxia type 3

ASJC Scopus subject areas

  • Neurology

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