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

• Published in: Neurobiology of disease Vol. 21; no. 2; pp. 333 - 345
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 2006
• Subjects: Apoptosis; Ataxin-3; Bax; Bcl-x L; Polyglutamine neurodegenerative disorders; Polyglutamine-expanded ataxin-3; Spinocerebellar ataxia type 3; Polyglutamine neurodegenerative disorders; Bcl-x L; Polyglutamine-expanded ataxin-3; Ataxin-3; Bax; Spinocerebellar ataxia type 3; Apoptosis
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2005.07.011

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-x L protein expression. Real-time TaqMan RT-PCR assays demonstrated that ataxin-3-Q79 upregulated Bax mRNA level and downregulated Bcl-x L 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-x L expression.