Structure of tau exon 10 splicing regulatory element RNA and destabilization by mutations of frontotemporal dementia and parkinsonism linked to chromosome 17 (alternative mRNA splicingyintronic mutationsystem-loop RNA structure)

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 thermo- dynamic stability is reduced by frontotemporal dementia and parkinsonism linked to chromosome 17 mutations and in- creased by compensatory mutations. By exon trapping, the reduction in thermodynamic stability is correlated with in- creased splicing in of exon 10.