title: Increase in the relative expression of tau with four microtubule binding repeat regions in frontotemporal lobar degeneration and progressive supranuclear palsy brains.
abstract: Some cases of familial frontotemporal dementia (FTD) leading to frontotemporal lobar degeneration (FTLD) are caused by mutations in tau on chromosome 17 (FTDP-17). Certain mutations alter the ratio between four (4R tau) and three (3R tau) repeat tau isoforms whereas cases with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) mainly have 4R tau brain pathology. We assessed tau mRNA and protein levels in frontal cortex from 15 sporadic FTLD, 21 PSP, 5 CBD, 15 Alzheimer's disease (AD) and 16 control brains. Moreover, we investigated the disease association and possible tau splicing effects of the tau H1 haplotype. Cases with FTLD and PSP had lower tau mRNA levels than control brains. When analyzing 4R tau and 3R tau mRNA separately, control subjects displayed a 4R tau/3R tau ratio of 0.48. Surprisingly, FTLD brains displayed a more elevated ratio (1.32) than PSP brains (1.12). Also, several FTLD and PSP cases had higher 4R tau/3R tau mRNA than FTDP-17 cases, included as reference tissues, and the ratio increase was seen regardless of underlying histopathology, i.e. both for tau-positive and tau-negative FTLD cases. Furthermore, total tau protein levels were slightly decreased in both FTLD and AD as compared to control subjects. Finally, we confirmed the association of tau H1 with PSP, but could not find any haplotype-related effect on tau exon 10 splicing. In conclusion, we demonstrated increased but largely variable 4R tau/3R tau mRNA ratios in FTLD and PSP cases, suggesting heterogeneous pathophysiological processes within these disorders.
authors.affiliation: Harvard Medical School, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA. martin.ingelsson@pubcare.uu.se
authors.forename: Martin
authors.initials: M
authors.lastname: Ingelsson
authors.forename: Karunya
authors.initials: K
authors.lastname: Ramasamy
authors.forename: Carsten
authors.initials: C
authors.lastname: Russ
authors.forename: Stefanie H
authors.initials: SH
authors.lastname: Freeman
authors.forename: Jennifer
authors.initials: J
authors.lastname: Orne
authors.forename: Susan
authors.initials: S
authors.lastname: Raju
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Matsui
authors.forename: John H
authors.initials: JH
authors.lastname: Growdon
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: Michael C
authors.initials: MC
authors.lastname: Irizarry
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004252:DNA Mutational Analysis; D003704:Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D013494:Supranuclear Palsy, Progressive / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018911:Trinucleotide Repeats / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D016875:tau Proteins