Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disease caused by polyglutamine-expanded ataxin-7. Prominent SCA7 neurodegeneration is found in the cerebellum and inferior olivary nucleus. Mutant polyglutamine ataxin-7 activated mitochondrial apoptotic pathway and induced apoptotic death of cerebellar and inferior olivary neurons by upregulating mRNA expression of proapoptotic Bax. In response to various cellular stresses, transcription factor p53 promotes neuronal apoptosis by enhancing the transcription of proapoptotic genes including Bax and Puma. Cellular and animal models of SCA7 were used to test the hypothesis that polyglutamine-expanded ataxin-7-Q52 upregulates Bax expression of cerebellar and inferior olivary neurons by enhancing transcriptional activity of p53. Electrophoretic mobility shift assay (EMSA) indicated that binding activity of p53 to Bax promoter sequence was significantly enhanced in cultured cerebellar neurons expressing mutant ataxin-7-Q52 and inferior olivary nucleus of transgenic mice expressing ataxin-7-Q52. The mRNA expression of Puma, a p53-inducible proapoptotic gene, was upregulated in cerebellar and inferior olivary neurons expressing ataxin-7-Q52. In the absence of significantly altered mRNA or protein expression of p53, mutant ataxin-7-Q52 increased the protein level of active phospho-p53(Ser15) in cerebellar and inferior olivary neurons. Our study provides the evidence that polyglutamine-expanded ataxin-7 upregulates the expression of Bax and Puma and causes apoptotic neuronal death by enhancing phosphorylation and transcriptional activity of p53.