title: Correction of alternative splicing of tau in frontotemporal dementia and parkinsonism linked to chromosome 17.
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.
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: B
authors.initials: B
authors.lastname: Kalbfuss
authors.forename: S A
authors.initials: SA
authors.lastname: Mabon
authors.forename: T
authors.initials: T
authors.lastname: Misteli
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002886:Chromosomes, Human, Pair 17; D003599:Cytoskeleton / Q000378:metabolism; D003704:Dementia / Q000235:genetics* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005091:Exons; D006801:Humans; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D009841:Oligonucleotides / Q000737:chemistry; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D016716:PC12 Cells; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism*; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism*
chemical_list: D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D016875:tau Proteins; D012313:RNA