Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL
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 adenoviruse...
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| Format: | Article |
| Language: | English |
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Elsevier
2006-02-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996105002123 |
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| author | 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 |
| author_facet | 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 |
| author_sort | An-Hsun Chou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T11:20:33Z |
| format | Article |
| id | doaj.art-e776351009d2461f9297d9314b6e34e4 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-14T11:20:33Z |
| publishDate | 2006-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-e776351009d2461f9297d9314b6e34e42022-12-21T23:03:46ZengElsevierNeurobiology of Disease1095-953X2006-02-01212333345Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xLAn-Hsun Chou0Tu-Hsueh Yeh1Yu-Li Kuo2Yu-Cheng Kao3Mei-Jie Jou4Chia-Yu Hsu5Shu-Ru Tsai6Akira Kakizuka7Hung-Li Wang8Department of Anesthesiology, Chang Gung Memorial Hospital, Taiwan, ROC; Graduate Institute of Clinical Medical Science, Chang Gung University School of Medicine, Kwei-San, Tao-Yuan, Taiwan, ROCDepartment of Neurology, Chang Gung Memorial Hospital, Taiwan, ROC; Graduate Institute of Clinical Medical Science, Chang Gung University School of Medicine, Kwei-San, Tao-Yuan, Taiwan, ROCDepartment of Physiology, Chang Gung University School of Medicine, Kwei-San, Tao-Yuan, Taiwan, ROCDepartment of Physiology, Chang Gung University School of Medicine, Kwei-San, Tao-Yuan, Taiwan, ROCDepartment of Pharmacology, Chang Gung University School of Medicine, Kwei-San, Tao-Yuan, Taiwan, ROCDepartment of Physiology, Chang Gung University School of Medicine, Kwei-San, Tao-Yuan, Taiwan, ROCDepartment of Physiology, Chang Gung University School of Medicine, Kwei-San, Tao-Yuan, Taiwan, ROCGraduate School of Biostudies, Kyoto University, Kyoto, JapanDepartment of Physiology, Chang Gung University School of Medicine, Kwei-San, Tao-Yuan, Taiwan, ROC; Corresponding author. Fax: +886 3 221 8700.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.http://www.sciencedirect.com/science/article/pii/S0969996105002123Spinocerebellar ataxia type 3Ataxin-3Polyglutamine-expanded ataxin-3ApoptosisPolyglutamine neurodegenerative disordersBax |
| spellingShingle | 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 Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL Neurobiology of Disease Spinocerebellar ataxia type 3 Ataxin-3 Polyglutamine-expanded ataxin-3 Apoptosis Polyglutamine neurodegenerative disorders Bax |
| title | Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL |
| title_full | Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL |
| title_fullStr | Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL |
| title_full_unstemmed | Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL |
| title_short | Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL |
| title_sort | polyglutamine expanded ataxin 3 activates mitochondrial apoptotic pathway by upregulating bax and downregulating bcl xl |
| topic | Spinocerebellar ataxia type 3 Ataxin-3 Polyglutamine-expanded ataxin-3 Apoptosis Polyglutamine neurodegenerative disorders Bax |
| url | http://www.sciencedirect.com/science/article/pii/S0969996105002123 |
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