Abstract
Mutations in the human tau gene cause frontotemporal dementia and Parkinsonism associated with chromosome 17 (FTDP-17). One of the major disease mechanisms in FTDP-17 is the increased inclusion of tau exon 10 during pre-mRNA splicing. Here we show that modified oligonucleotides directed against the tau exon 10 splice junctions suppress inclusion of tau exon 10. The effect is mediated by the formation of a stable pre-mRNA-oligonucleotide hybrid, which blocks access of the splicing machinery to the pre-mRNA. Correction of tau splicing occurs in a tau minigene system and in endogenous tau RNA in neuronal pheochromocytoma cells and is specific to exon 10 of the tau gene. Antisense oligonucleotide-mediated exclusion of exon 10 has a physiological effect by increasing the ratio of protein lacking the microtubule-binding domain encoded by exon 10. As a consequence, the microtubule cytoskeleton becomes destabilized and cell morphology is altered. Our results demonstrate that alternative splicing defects of tau as found in FTDP-17 patients can be corrected by application of antisense oligonucleotides. These findings provide a tool to study specific tau isoforms in vivo and might lead to a novel therapeutic strategy for FTDP-17.
Highlights
Apart from FTDP-17, tau deposits are the defining pathological feature of several neurological disorders including Alzheimer’s disease, progressive supranuclear palsy, and Niemann-Pick disease [4, 6]
Our rationale was that the oligonucleotides prevent access of the splicing machinery to the splice junction and in this way may block the inclusion of the protected tau exon 10 into the mRNA (Fig. 1, a and c)
Exclusion of Tau Exon 10 in a Minigene System—To test whether antisense oligonucleotides targeted to tau exon 10 sequences were capable of altering the splicing behavior of tau exon 10, we used a previously characterized minigene system that recapitulates to a large extent the behavior of exon 10 in the context of the full-length tau gene [21]
Summary
Vol 276, No 46, Issue of November 16, pp. 42986 –42993, 2001 Printed in U.S.A. Correction of Alternative Splicing of Tau in Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17*. One of the major disease mechanisms in FTDP-17 is the increased inclusion of tau exon 10 during pre-mRNA splicing. Our results demonstrate that alternative splicing defects of tau as found in FTDP-17 patients can be corrected by application of antisense oligonucleotides. These findings provide a tool to study specific tau isoforms in vivo and might lead to a novel therapeutic strategy for FTDP-17. One of the diseases directly caused by mutations that result in pre-mRNA splicing defects is frontotemporal dementia and Parkinsonism associated with chromosome 17 (FTDP-17) (4 – 6). The oligonucleotides elicited a physiological effect by reducing the level of tau protein containing the microtubule-binding domain encoded by exon 10, and as a consequence the cytoskeleton morphology was altered. The use of antisense oligonucleotides will be useful to study the physiological role of specific tau isoforms in disease and cellular differentiation, and it might provide a novel therapeutic strategy to treat FTDP-17 and other tauopathies
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