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J. Biol. Chem., Vol. 281, Issue 33, 23302-23306, August 18, 2006

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Stabilization of the Tau Exon 10 Stem Loop Alters Pre-mRNA Splicing^*

Christine P. Donahue, Christina Muratore, Jane Y. Wu, Kenneth S. Kosik^¶, and Michael S. Wolfe¹

From the Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, the Center for Genetic Medicine, Northwestern University Feinberg Medical School, Chicago, Illinois 60611, and the ^¶Neuroscience Research Institute, University of California, Santa Barbara, California 93106

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 minigene 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.

Received for publication, June 2, 2006 , and in revised form, June 16, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Center for Neurologic Diseases, Brigham and Women's Hospital, 77 Ave. Louis Pasteur, Boston, MA 02115. Tel.: 617-525-5511; Fax: 617-525-5252; E-mail: mwolfe{at}rics.bwh.harvard.edu.

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