Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL

An Hsun Chou, Tu Hsueh Yeh, Yu Li Kuo, Yu Cheng Kao, Mei Jie Jou, Chia Yu Hsu, Shu Ru Tsai, Akira Kakizuka, Hung Li Wang

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disease caused by polyglutamine-expanded ataxin-3. In the present study, we expressed disease-causing mutant ataxin-3-Q79 in neuronal cultures of cerebellum, striatum and substantia nigra by using recombinant adenoviruses. Subsequently, SCA3 cellular model was used to investigate the molecular mechanism by which ataxin-3-Q79 causes neuronal death. TUNEL staining studies showed that ataxin-3-Q79 induced apoptotic death of cerebellar, striatal or substantia nigra neurons. Ataxin-3-Q79 activated caspase-3 and caspase-9 without inducing the formation of active caspase-8. Ataxin-3-Q79 promoted mitochondrial release of cytochrome c and Smac, which was preceded by the upregulation of Bax protein and downregulation of Bcl-xL protein expression. Real-time TaqMan RT-PCR assays demonstrated that ataxin-3-Q79 upregulated Bax mRNA level and downregulated Bcl-xL mRNA expression in striatal, cerebellar and substantia nigra neurons. Our results suggest that polyglutamine-expanded ataxin-3-Q79 activates mitochondrial apoptotic pathway and induces neuronal death by upregulating Bax expression and downregulating Bcl-xL expression.

Original languageEnglish
Pages (from-to)333-345
Number of pages13
JournalNeurobiology of Disease
Volume21
Issue number2
DOIs
Publication statusPublished - Feb 2006
Externally publishedYes

Fingerprint

Down-Regulation
Substantia Nigra
Machado-Joseph Disease
Corpus Striatum
Neurons
bcl-2-Associated X Protein
Messenger RNA
Ataxin-3
polyglutamine
Caspase 9
Caspase 8
In Situ Nick-End Labeling
Cytochromes c
Adenoviridae
Caspase 3
Neurodegenerative Diseases
Cerebellum
Cause of Death
Up-Regulation
Staining and Labeling

Keywords

  • Apoptosis
  • Ataxin-3
  • Bax
  • Bcl-x
  • Polyglutamine neurodegenerative disorders
  • Polyglutamine-expanded ataxin-3
  • Spinocerebellar ataxia type 3

ASJC Scopus subject areas

  • Neurology

Cite this

Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL. / Chou, An Hsun; Yeh, Tu Hsueh; Kuo, Yu Li; Kao, Yu Cheng; Jou, Mei Jie; Hsu, Chia Yu; Tsai, Shu Ru; Kakizuka, Akira; Wang, Hung Li.

In: Neurobiology of Disease, Vol. 21, No. 2, 02.2006, p. 333-345.

Research output: Contribution to journalArticle

Chou, An Hsun ; Yeh, Tu Hsueh ; Kuo, Yu Li ; Kao, Yu Cheng ; Jou, Mei Jie ; Hsu, Chia Yu ; Tsai, Shu Ru ; Kakizuka, Akira ; Wang, Hung Li. / Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL. In: Neurobiology of Disease. 2006 ; Vol. 21, No. 2. pp. 333-345.
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