title: Polyglutamine-expanded ataxin-7 activates mitochondrial apoptotic pathway of cerebellar neurons by upregulating Bax and downregulating Bcl-x(L).
abstract: Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder caused by polyglutamine-expanded ataxin-7. In the present investigation, we expressed disease-causing mutant ataxin-7-Q75 in the primary neuronal culture of cerebellum with the aid of recombinant adenoviruses. Subsequently, this in vitro cellular model of SCA7 was used to study the molecular mechanism by which mutant ataxin-7-Q75 induces neuronal death. TUNEL staining studies indicated that polyglutamine-expanded ataxin-7-Q75 caused apoptotic cell death of cultured cerebellar neurons. Mutant ataxin-7-Q75 induced the formation of active caspase-3 and caspase-9 without activating caspase-8. Polyglutamine-expanded ataxin-7-Q75 promoted the release of apoptogenic cytochrome-c and Smac from mitochondria, which was preceded by the downregulation of Bcl-x(L) protein and upregulation of Bax protein expression in cultured cerebellar neurons. Further real-time TaqMan RT-PCR assays showed that mutant ataxin-7-Q75 upregulated Bax mRNA level and downregulated Bcl-x(L) mRNA expression in the primary neuronal culture of cerebellum. The present study provides the evidence that polyglutamine-expanded ataxin-7-Q75 activates mitochondria-mediated apoptotic cascade and induces neuronal death by upregulating Bax expression and downregulating Bcl-x(L) expression of cerebellar neurons.
authors.affiliation: Department of Physiology, Chang Gung University School of Medicine, Kwei-San, Tao-Yuan, Taiwan, ROC. hlwns@mail.cgu.edu.tw
authors.forename: Hung-Li
authors.initials: HL
authors.lastname: Wang
authors.forename: Tu-Hsueh
authors.initials: TH
authors.lastname: Yeh
authors.forename: An-Hsun
authors.initials: AH
authors.lastname: Chou
authors.forename: Yu-Li
authors.initials: YL
authors.lastname: Kuo
authors.forename: Li-Jean
authors.initials: LJ
authors.lastname: Luo
authors.forename: Cai-Ying
authors.initials: CY
authors.lastname: He
authors.forename: Pei-Chen
authors.initials: PC
authors.lastname: Huang
authors.forename: Allen H
authors.initials: AH
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D000067719:Ataxin-7; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000378:metabolism*; D051020:bcl-X Protein / Q000187:drug effects / Q000378:metabolism*
chemical_list: C000593829:ATXN7 protein, human; D051017:Apoptosis Regulatory Proteins; D000067719:Ataxin-7; C000593832:Atxn7 protein, rat; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C097188:polyglutamine; D045304:Cytochromes c; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases