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

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)573-581
Number of pages9
JournalCellular Signalling
Volume19
Issue number3
DOIs
Publication statusPublished - Mar 2007
Externally publishedYes

Keywords

  • Ataxin-7
  • Cerebellum
  • NF-κB
  • Polyglutamine-expanded ataxin-7
  • Proteasome
  • Spinocerebellar ataxia type 7

ASJC Scopus subject areas

  • Cell Biology

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