title: Neurodegenerative disorder FTDP-17-related tau intron 10 +16C → T mutation increases tau exon 10 splicing and causes tauopathy in transgenic mice.
abstract: Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a neurodegenerative disorder caused by mutations in the tau gene. Many mutations identified in FTDP-17 have been shown to affect tau exon 10 splicing in vitro, which presumably causes pathologic imbalances in exon 10(-) [3-repeat (3R)] and exon 10(+) [4-repeat (4R)] tau expression and leads to intracellular inclusions of hyperphosphorylated tau in patient brains. However, no reports have investigated this theory using model mice with a tau intronic mutation. Herein, we generated new transgenic mice harboring the tau intron 10 +16C → T mutation. We prepared a transgene construct containing intronic sequences required for exon 10 splicing in the longest tau isoform cDNA. Although mice bearing the construct without the intronic mutation showed normal developmental changes of the tau isoform from 3R tau to equal amounts of 3R and 4R tau, mice with the mutation showed much higher levels of 4R tau at the adult stage. 4R tau was selectively recovered in insoluble brain fractions in their old age. Furthermore, these mice displayed abnormal tau phosphorylation, synapse loss and dysfunction, memory impairment, glial activation, tangle formation, and neuronal loss in an age-dependent manner. These findings provide the first evidence in a mouse model that a tau intronic mutation-induced imbalance of 3R and 4R tau could be a cause of tauopathy.
authors.affiliation: Department of Neuroscience, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Umeda
authors.forename: Takenari
authors.initials: T
authors.lastname: Yamashita
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kimura
authors.forename: Kiyouhisa
authors.initials: K
authors.lastname: Ohnishi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takuma
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ozeki
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takashima
authors.forename: Takami
authors.initials: T
authors.lastname: Tomiyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mori
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005091:Exons; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005819:Genetic Markers; D007438:Introns; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D012326:RNA Splicing; D020133:Reverse Transcriptase Polymerase Chain Reaction; D024801:Tauopathies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016875:tau Proteins / Q000235:genetics*
chemical_list: D005819:Genetic Markers; C558298:Mapt protein, mouse; D016875:tau Proteins