High Prevalence of Mutations in the Microtubule-Associated Protein Tau in a Population Study of Frontotemporal Dementia in the Netherlands

Abstract

Mutations in microtubule-associated protein tau recently have been identified in familial cases of frontotemporal dementia (FTD). We report the frequency of tau mutations in a large population-based study of FTD carried out in the Netherlands from January 1994 to June 1998. Thirty-seven patients had >/=1 first-degree relative with dementia. A mutation in the tau gene was found in 17.8% of the group of patients with FTD and in 43% of patients with FTD who also had a positive family history of FTD. Three distinct missense mutations (G272V, P301L, R406W) accounted for 15.6% of the mutations. These three missense mutations, and a single amino acid deletion (DeltaK280) that was detected in one patient, strongly reduce the ability of tau to promote microtubule assembly. We also found an intronic mutation at position +33 after exon 9, which is likely to affect the alternative splicing of tau. Tau mutations are responsible for a large proportion of familial FTD cases; however, there are also families with FTD in which no mutations in tau have been found, which indicates locus and/or allelic heterogeneity. The different tau mutations may result in disturbances in the interactions of the protein tau with microtubules, resulting in hyperphosphorylation of tau protein, assembly into filaments, and subsequent cell death.

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

“…Barghorn and colleagues showed that the ΔK280 4R-tau protein has a 5-fold greater rate of aggregation compared to wild-type 4R-tau and, "since PHF assembly is a nucleation-dependent process, nuclei formed by mutant tau could be elongated even from the pool of normal tau and thus poison the entire tau population in a cell" (Barghorn et al, 2000). This would be compounded by the strongly reduced capacity of the ΔK280 tau variant to promote microtubule assembly (Rizzu et al, 1999).…”

“…tau transcript, which would be predicted to occur in very small amounts since the mutation is in exon 10 and thus would be expected to be largely self-excluding, is extremely fibrillogenic and has frequently been used to model tau aggregation (Barghorn et al, 2000;Mukrasch et al, 2005;Vogelsberg-Ragaglia et al, 2005;von Bergen et al, 2001). Furthermore, it has been demonstrated to strongly reduce the ability of tau to promote microtubule assembly (Rizzu et al, 1999). 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).…”

“…Furthermore, it has been demonstrated to strongly reduce the ability of tau to promote microtubule assembly (Rizzu et al, 1999). 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).…”

The granulin gene family: from cancer to dementia

“…Other mutations in addition to GRN cause FTD, most notably the microtubuleassociated protein tau (MAPT), (55) and, more rarely, chromatinmodifying protein 2B (CHMP2B) (56) and the valosin-containing protein (VCP). (57) MAPT was the first FTD gene to be identified, and maps in remarkably close proximity to GRN on chromosome 17q21.3.…”

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.…”