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.
ASJC Scopus subject areas
- Cell Biology
Wang, H. L., He, C. Y., Chou, A. H., Yeh, T. H., Chen, Y. L., & Li, A. H. L. (2007). Polyglutamine-expanded ataxin-7 decreases nuclear translocation of NF-κB p65 and impairs NF-κB activity by inhibiting proteasome activity of cerebellar neurons. Cellular Signalling, 19(3), 573-581. https://doi.org/10.1016/j.cellsig.2006.08.006