5 ' splice site mutations in tau associated with the inherited dementia FTDP-17 affect a stem-loop structure that regulates alternative splicing of exon 10

Missense and splice site mutations in the microtubule-associated protein ta u gene were recently found associated with fronto-temporal dementia and par kinsonism linked to chromosome 17 (Poorkaj et al. (1998) Ann. Neurol. 43, 8 15-825; Hutton et al. (1998) Nature 393, 702-705; Spillantini et al. (1998) Proc. Natl Acad Sci. U.S.A 95, 7737-7741). The mutations in the 5' splice site of exon 10 were shown to increase the ratio of tau mRNAs containing ex on 10 and thus the proportion of Tau protein isoforms with 4 microtubule bi nding repeat domains, although how this increase leads to neurodegeneration is presently unclear. The mechanism by which these mutations increase tau exon 10 splicing was not determined, although the mutations were predicted to disrupt a potential stem-loop structure that was likely involved in the regulation of exon 10 alternative splicing. Here we describe in vitro splic ing assays and RNA structural analysis that demonstrate that the mutations do indeed act through disruption of the stem-loop structure and that the st ability of this secondary structure feature at least partially determines t he ratio of tau exon 10+/- transcripts. In addition, we provide evidence th at the stability of the stem-loop structure underlies the alternative splic ing of this exon in other species.