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Papers In Press, published online ahead of print June 16, 2006
Center for Neurodegenerative Disease, Brigham & Women's Hosptial/Harvard Medical School, Boston, MA 02115
Corresponding Author: mwolfe{at}rics.bwh.harvard.edu
Neurofibrillary tangles containing filaments of the microtubule-associated protein tau are found in a variety of neurodegenerative diseases. Mutations in the tau gene itself cause frontotemporal dementia with parkinsonism, demonstrating the critical role of tau in pathogenesis. Many of these mutations in tau are silent, are found at the 5’-splice site of exon 10, and lead to increased inclusion of exon 10. These silent mutations are predicted to destabilize a stem loop structure at the exon 10 5’ splice site; however, the existence of this stem loop under physiological conditions and its role in splice regulation are controversial. Here we show that base changes that stabilize this stem loop in vitro substantially decrease exon 10 inclusion in a wild type tau mini-gene and rescue the increase in exon 10 splicing caused by a dementia-causing point mutation. Moreover, we probed the intracellular structure of the tau stem loop with antisense RNA and demonstrate that the stability of the stem loop dictates antisense effectiveness. Together these results validate the stem loop as a bona fide structure regulating tau exon 10 splicing.
J. Biol. Chem, 10.1074/jbc.C600143200
Submitted on June 2, 2006
Revised on June 16, 2006
Accepted on June 16, 2006
Stabilization of the TAU exon 10 stem loop alters pre-mRNA splicing
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