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

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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

Fingerprint

Cerebellar Diseases
Transgenic Mice
Cerebellum
Messenger RNA
Ataxin-3
polyglutamine
Down-Regulation
Cerebellar Ataxia
Calcium Signaling
Cyclin D1
Substantia Nigra
Pathologic Processes
GABA-A Receptors
Ataxia
Microarray Analysis
Heat-Shock Proteins
Age of Onset
Synaptic Transmission
Genes
Real-Time Polymerase Chain Reaction

Keywords

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

ASJC Scopus subject areas

  • Neurology

Cite this

Polyglutamine-expanded ataxin-3 causes cerebellar dysfunction of SCA3 transgenic mice by inducing transcriptional dysregulation. / Chou, An Hsun; Yeh, Tu Hsueh; Ouyang, Pin; Chen, Ying Ling; Chen, Si Ying; Wang, Hung Li.

In: Neurobiology of Disease, Vol. 31, No. 1, 07.2008, p. 89-101.

Research output: Contribution to journalArticle

Chou, An Hsun ; Yeh, Tu Hsueh ; Ouyang, Pin ; Chen, Ying Ling ; Chen, Si Ying ; Wang, Hung Li. / Polyglutamine-expanded ataxin-3 causes cerebellar dysfunction of SCA3 transgenic mice by inducing transcriptional dysregulation. In: Neurobiology of Disease. 2008 ; Vol. 31, No. 1. pp. 89-101.
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