PMID- 17204933
OWN - NLM
STAT- MEDLINE
DCOM- 20070215
LR  - 20131121
IS  - 0022-3069 (Print)
IS  - 0022-3069 (Linking)
VI  - 66
IP  - 1
DP  - 2007 Jan
TI  - The DeltaK280 mutation in MAP tau favors exon 10 skipping in vivo.
PG  - 17-25
AB  - Tau mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 
      (FTDP-17) are associated with changes in alternative splicing of exon 10. The 
      DeltaK280 mutation in exon 10 is exceptional because in vitro observations 
      suggest a dramatic effect on microtubule binding, enhanced self-aggregation, as 
      well as a decrease of the 4R/3R ratio by the ablation of an exon splicing 
      enhancer element. Using immunohistochemistry, Western blotting, and electron 
      microscopy on brain material with the DeltaK280 mutation, we investigated which 
      of these effects is most dominant in vivo. The brain showed abundant Pick bodies 
      in several brain regions, which stained positive with 3-repeat-specific but not 
      with 4-repeat-specific tau antibodies. Western blots of sarkosyl-insoluble tau 
      showed exclusively three repeat (3R0N and 3R1N) tau in most regions, although 
      some 4R1N could be detected in the frontal cortex. In addition, the 
      sarkosyl-soluble tau fraction showed a significantly higher amount of 3-repeat 
      tau. Because quantitative analysis of 4R and 3R mRNA transcripts showed a 4R/3R 
      ratio of only 0.3, association between increased transcription and protein 
      expression was observed. These observations confirm the postulated hypothesis 
      that the DeltaK280 mutation abolishes a splice enhancer element, which overrules 
      the decreased microtubule binding and enhanced self-aggregation.
FAU - van Swieten, John C
AU  - van Swieten JC
AD  - Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands. 
      j.c.vanswieten@erasmusmc.nl
FAU - Bronner, Iraad F
AU  - Bronner IF
FAU - Azmani, Asma
AU  - Azmani A
FAU - Severijnen, Lies-Anne
AU  - Severijnen LA
FAU - Kamphorst, Wouter
AU  - Kamphorst W
FAU - Ravid, Rivka
AU  - Ravid R
FAU - Rizzu, Patrizia
AU  - Rizzu P
FAU - Willemsen, Rob
AU  - Willemsen R
FAU - Heutink, Peter
AU  - Heutink P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Neuropathol Exp Neurol
JT  - Journal of neuropathology and experimental neurology
JID - 2985192R
RN  - 0 (tau Proteins)
RN  - 452VLY9402 (Serine)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
MH  - Alzheimer Disease/metabolism/pathology
MH  - Blotting, Western/methods
MH  - Brain/metabolism/pathology/ultrastructure
MH  - Dementia/*genetics/pathology
MH  - *Exons
MH  - Female
MH  - Humans
MH  - Immunohistochemistry/methods
MH  - Lysine/*genetics
MH  - Microscopy, Electron, Transmission/methods
MH  - Middle Aged
MH  - Molecular Weight
MH  - *Mutation
MH  - Neurons/metabolism/pathology
MH  - Serine/metabolism
MH  - Trinucleotide Repeat Expansion/genetics
MH  - tau Proteins/*genetics
EDAT- 2007/01/06 09:00
MHDA- 2007/02/16 09:00
CRDT- 2007/01/06 09:00
PHST- 2007/01/06 09:00 [pubmed]
PHST- 2007/02/16 09:00 [medline]
PHST- 2007/01/06 09:00 [entrez]
AID - 00005072-200701000-00003 [pii]
AID - 10.1097/nen.0b013e31802c39a4 [doi]
PST - ppublish
SO  - J Neuropathol Exp Neurol. 2007 Jan;66(1):17-25. doi: 
      10.1097/nen.0b013e31802c39a4.