The ΔK280 Mutation in MAP tau Favors Exon 10 Skipping In Vivo

Abstract

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.

Clinical and pathological features of an Alzheimer's disease patient with the MAPT ΔK280 mutation

“…There was extensive pathology with gross and microscopic evidence of Alzheimer disease, dementia with Lewy bodies and vascular dementia. In contrast to the previously described case with a ΔK280 mutation (van Swieten et al, 2007), which had severe atrophy of the frontal and temporal cortex extending into the inferior parietal lobe, the present case showed no evidence of frontotemporal degeneration.…”

“…No Pick bodies or ballooned Pick cells were seen in the hippocampus or in any other location. On the other hand, the other ΔK280 case described by van Swieten and co-workers (van Swieten et al, 2007) demonstrated relatively widespread Pick bodies and also, taupositive glial cells.…”

“…In addition, the original report of the occurrence of this mutation, in a Dutch individual with sporadic FTD, but with a father with reported Parkinson's disease, was very circumspect and did not claim that this mutation was pathogenic (Rizzu et al, 1999). A follow up of this original report has recently been published, showing that the tau deposition in this individual is largely in the form of Pick bodies, and that the predominant tau isoform deposited was 3R-tau but that some 4R-tau was also found (van Swieten et al 2007). …”

Interplay of pathogenic forms of human tau with different autophagic pathways

“…We included the following: (i) deletion of lysine 280 (ΔK280) (Rizzu et al ., 1999; Momeni et al ., 2009), which leads to excess of 3R transcripts (van Swieten et al ., 2007) and enhances tau aggregation into PHFs (Rizzu et al ., 1999; Barghorn et al ., 2000); (ii) mutations in cysteines 291 and 322 (C291 and C322), whose oxidation increases propensity of tau aggregation (Barghorn & Mandelkow, 2002; Mo et al ., 2009); and (iii) mutations that mimic or disrupt phosphorylation in residues previously related to tau toxicity or aggregation propensity (Biernat & Mandelkow, 1999). We have found that these modifications have a different impact on the degradation of tau by each of the autophagic pathways, and on the way in which they affect functioning of these autophagic pathways.…”

A simple algorithm locates β‐strands in the amyloid fibril core of α‐synuclein, Aβ, and tau using the amino acid sequence alone

“…About half of the known mutations in tau influence the splicing of tau pre-mRNA, mostly resulting in a higher ratio of 4R-to 3R-tau, but occasionally resulting in a lower ratio (Goedert and Spillantini 2006;van Swieten et al 2007). A complete understanding of how this ratio influences the onset of a tauopathy is currently lacking.…”