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

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

^*Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom; ^†Department of Neurology, E. D. Adrian Building, University of Cambridge, Robinson Way, Cambridge CB2 2PY, United Kingdom; and ^‡Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 47202

Contributed by Aaron Klug

Abstract

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.

Footnotes

↵ § To whom reprint requests should be addressed. e-mail: gv1{at}mrc-lmb.cam.ac.uk.
Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.rcsb.org (PDB ID code 1Qc8).
ABBREVIATIONS:

FTDP-17,

frontotemporal dementia and parkinsonism linked to chromosome 17;

NOE,

nuclear Overhauser effect