Abstract
Mutations in the tau gene are pathogenic causing autosomal dominant frontotemporal dementia with Parkinsonism-chromosome 17 type (FTDP-17). Some mutations in tau exon 10 (E10) and immediately adjacent sequences cause disease by altering E10 splicing. To determine the mechanism of normal E10 splicing regulation and how FTDP-17 mutations alter splicing, mutational analysis of E10 was performed. The results show that E10 contains a complex array of both enhancer and inhibitor cis-acting elements that modulate usage of a weak 5' splice site. The 5' end of E10 contains a previously unrecognized multipartite exon splicing enhancer (ESE) composed of an SC35-like binding sequence, a purine-rich sequence, and an AC-rich element. Downstream of this ESE is a purine-rich exon splicing inhibitor. Intronic sequences immediately downstream of E10 also are inhibitory. The results support an alternative model in which I10 inhibitory sequences appear to function as a linear sequence. The cis-elements described are not redundant, and all appear required for normal E10 splicing. Results with double mutations demonstrate that the ESE and the intronic inhibitory element collaborate to regulate splicing. Thus splicing of tau E10 is regulated by a complex set of cis-acting elements that span nearly the entire exon and also include intronic sequences.
Highlights
Mutations in the tau gene are pathogenic causing autosomal dominant frontotemporal dementia with Parkinsonism-chromosome 17 type (FTDP-17)
Previous work on the effects of FTDP-17 mutations on tau exon 10 (E10) splicing showed that mutations at nucleotides 15–18 within a purine-rich region in E10 and a mutation at nucleotide 30 altered splicing of this exon [15]
To identify the regulatory elements affected by these mutations and to reveal other potential regulatory sequences, we generated in-frame 3 nucleotide deletions from the beginning of E10 exon to nucleotide 33 (ED1–ED11)
Summary
E10, exon 10; 3R, 3-repeat tau; 4R, 4-repeat tau; ACE, A/C-rich enhancer; AD, Alzheimer’s disease; ESE, exon splicing enhancer; ESS, exon splicing silencer; FTDP-17, frontothat is repeated 3 times in tau isoforms lacking E10 sequences (3 repeat or 3R tau) and 4 times when E10 is present (4R tau). The L284L E10 silent mutation and intron 10 (I10) mutations immediately adjacent to the 39 end of E10 increase E10 inclusion [6, 15] Another FTDP-17 mutation, an in-frame 3-base deletion in E10 (D280K), is unique in that it alters tau protein function and completely abolishes E10 inclusion in tau transcripts [15, 17]. As temporal dementia with Parkinsonism-chromosome 17 type; I9, intron 9; I10, intron 10; ISS, intron splicing silencer; MCS, multiple cloning site; PPE, polypurine enhancer; SR, Arg/Ser-rich splicing factors; PCR, polymerase chain reaction; RT-PCR, reverse transcription-PCR; bp, base pair; HIV, human immunodeficiency virus; snRNP, small nuclear ribonucleoprotein. Different mutations that increase E10 usage result in different clinical and neuropathologic phenotypes, presumably because these mutations affect different cis-acting regulatory elements controlling E10 splicing. Correct regulation of tau E10 is the result of contributions from each of these elements
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