Polyglutamine-expanded ataxin-7 decreases nuclear translocation of NF-κB p65 and impairs NF-κB activity by inhibiting proteasome activity of cerebellar neurons

Hung Li Wang, Cai Ying He, An Hsun Chou, Tu Hsueh Yeh, Ying Ling Chen, Allen Hon Lun Li

研究成果: 雜誌貢獻文章

15 引文 斯高帕斯(Scopus)

摘要

Our recent study indicated that polyglutamine-expanded ataxin-7-Q75 induced apoptotic death of cultured cerebellar neurons by downregulating Bcl-xL expression and activating mitochondrial apoptotic cascade. Mutant polyglutamine-expanded proteins are believed to impair the proteolytic function of ubiquitin-proteasome system by sequestering components of proteasomes. Proteasome degradation of IκBα permits nuclear translocation of NF-κB and is required for continuous NF-κB activity, which supports the survival of cultured cerebellar neurons by inducing Bcl-xL expression. Thus, we tested the hypothesis that mutant ataxin-7-Q75 causes proteasome dysfunction and impairs NF-κB activity, leading to reduced Bcl-xL expression, caspase activation and cerebellar neuronal death. EMSA assays indicate that DNA-binding activity of NF-κB was significantly decreased in cerebellar neurons expressing ataxin-7-Q75. Similar to mutant ataxin-7-Q75, NF-κB inhibitor APEQ induced cerebellar neuronal death by decreasing Bcl-xL expression and activating caspase-9. Mutant ataxin-7-Q75 inhibited the proteolytic activity of proteasomes in cerebellar neurons. Proteasome inhibitor MG132 also caused cerebellar neuronal death by decreasing Bcl-xL expression and activating caspase-9. Both ataxin-7-Q75 and MG132 caused the cytosolic accumulation of IκBα in cerebellar neurons. Mutant ataxin-7-Q75 or MG132 increased the cytosolic level of NF-κB p65 and decreased the nuclear NF-κB p65 level. Our study provides the evidence that polyglutamine-expanded ataxin-7-Q75 decreases nuclear translocation of NF-κB p65 and impairs NF-κB activity by inhibiting proteasome activity of cerebellar neurons.
原文英語
頁(從 - 到)573-581
頁數9
期刊Cellular Signalling
19
發行號3
DOIs
出版狀態已發佈 - 三月 2007
對外發佈Yes

ASJC Scopus subject areas

  • Cell Biology

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