Structure of tau exon 10 splicing regulatory element RNA and destabilization by mutations of frontotemporal dementia and parkinsonism linked to chromosome 17

被引:210
作者
Varani, L
Hasegawa, M
Spillantini, MG
Smith, MJ
Murrell, JR
Ghetti, B
Klug, A
Goedert, M
Varani, G
机构
[1] MRC, Mol Biol Lab, Cambridge CB2 2QH, England
[2] Univ Cambridge, Dept Neurol, Cambridge CB2 2PY, England
[3] Indiana Univ, Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 47202 USA
关键词
alternative mRNA splicing; intronic mutations; stem-loop RNA structure;
D O I
10.1073/pnas.96.14.8229
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Coding region and intronic mutations in the tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17. Intronic mutations and some missense mutations increase splicing in of exon 10, leading to an increased ratio of four-repeat to three-repeat tau isoforms. Secondary structure predictions have led to the proposal that intronic mutations and one missense mutation destabilize a putative RNA stem-loop structure located close to the splice-donor site of the intron after exon 10. We have determined the three-dimensional structure of this tau exon 10 splicing regulatory element RNA by NMR spectroscopy. We show that it forms a stable, folded stem-loop structure whose thermodynamic stability is reduced by frontotemporal dementia and parkinsonism linked to chromosome 17 mutations and increased by compensatory mutations. By exon trapping, the reduction in thermodynamic stability is correlated with increased splicing in of exon 10.
引用
收藏
页码:8229 / 8234
页数:6
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