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 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-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.
Chou
An-Hsun
AH
Department of Anesthesiology, Chang Gung Memorial Hospital, Taiwan, ROC.
Yeh
Tu-Hsueh
TH
Kuo
Yu-Li
YL
Kao
Yu-Cheng
YC
Jou
Mei-Jie
MJ
Hsu
Chia-Yu
CY
Tsai
Shu-Ru
SR
Kakizuka
Akira
A
Wang
Hung-Li
HL
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D000067699:Ataxin-3; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D020287:In Situ Nick-End Labeling; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins; D010455:Peptides / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020754:Spinocerebellar Ataxias / Q000473:pathology / Q000503:physiopathology*; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*
D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012333:RNA, Messenger; D012097:Repressor Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C511593:Atxn3 protein, rat