Tau mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) are associated with changes in alternative splicing of exon 10. The ΔK280 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 ΔK280 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 ΔK280 mutation abolishes a splice enhancer element, which overrules the decreased microtubule binding and enhanced self-aggregation.

Additional Metadata
Keywords 3-repeat tauopathy, Pick disease, Tau mutation
Persistent URL dx.doi.org/10.1097/nen.0b013e31802c39a4, hdl.handle.net/1765/35665
Journal Journal of Neuropathology and Experimental Neurology
van Swieten, J.C, Bronner, I.F, Azmani, A, Severijnen, E.A.W.F.M, Kamphorst, W, Ravid, R, … Heutink, P. (2007). The ΔK280 mutation in MAP tau favors exon 10 skipping in vivo. Journal of Neuropathology and Experimental Neurology, 66(1), 17–25. doi:10.1097/nen.0b013e31802c39a4