部分DRPLA蛋白一過性発現系におけるCREB依存性転写障害の研究
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概要
- 論文の詳細を見る
Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant progressive neurodegenerative disorder caused by unstable expansion of a CAG trinucleotide repeat in exon 5 of the DRPLA gene on chomosome12p13.31, which codes for a polyglutamine stretch. To elucidate the mechanisms of neurodegeneration in DRPLA, suppression of CRE-binding protein (CREB)-dependent transcriptional activation by expanded polyglutamine (polyQ) stretches was analyzed. Phosphorylation of CREB and induction of c-Fos in response to CPT-cAMP were strongly suppressed in Neuro2a cells expressing expanded polyQ in a polyQ-length-dependent manner. The suppression of CREB-dependent transcriptional activation was reversibly restored by increasing the concentration of CPT-cAMP. Expanded polyQ-induced cytotoxicity determined by quantiation of nuclear fragmentation was also substantially suppressed by enhancing CREB-dependent transcriptional activation. FR901228, a histone deacetylase inhibitor, was also demonstrated to restore expanded polyQ-induced suppression of CREB phosphorylation and c-Fos expression. Furthermore, nuclear fragmentation was significantly suppressed by FR901228. Coexpression of dominant-negative CREB vectors considerably abrogated the suppressive effect of CPT-cAMP as well as FR901228 on the expanded polyQ-induced cytotoxicity. These findings suggest that the interference of CREB-dependent transcriptional activation by expanded polyQ stretches is involved in the pathogenetic mechanisms underlying neurodegeneration, and that enhancement of CREB-dependent transcriptional activation is a target of treatment of polyglutamine diseases.
- 新潟大学の論文
- 2003-10-10