Tau mutations in familial frontotemporal dementia.

The discovery of close to 20 different mutations in the gene encoding the microtubule-associated protein tau in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has shown that dysfunction of tau protein causes neurodegeneration and dementia (Hutton et al., 1998; Poorkaj et al., 1998; Spillantini et al., 1998; reviewed in Spillantini et al., 2000). It has implications for an understanding of Alzheimer’s disease (AD), Pick’s disease (PD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). All these diseases are characterized neuropathologically by an abundant filamentous tau pathology in nerve cells and, for some, in glial cells. The paper by Stanford and colleagues published in this issue of Brain is the latest in a series of studies reporting novel mutations in the tau gene in FTDP-17 (Stanford et al., 2000). It adds to our understanding of how tau mutations lead to neurodegeneration and throws light on the pathogenesis of PSP. Six tau isoforms are expressed in adult human brain by alternative mRNA splicing from a single gene (Fig. 1). They differ from each other by the presence or absence of three inserts encoded by exons 2, 3 and 10. Inclusion of exon 10 gives rise to the three tau isoforms with four repeats each. The other three isoforms have three repeats each. Normal adult human brain expresses similar levels of threeand four-repeat tau isoforms. The repeats and some adjoining sequences constitute the microtubule-binding domains of tau. Tau protein promotes microtubule assembly and binds to microtubules, which are stabilized as a result. Tau mutations in FTDP-17 are either missense, deletion or silent mutations in the coding region, or intronic mutations located close to the splice-donor site of the intron following exon 10 (Fig. 1) (Spillantini et al., 2000). Coding region mutations are located in the microtubule-binding repeat region, or close to it. Mutations in exon 9 (G272V), exon 12 (V337M) and exon 13 (G389R and R406W) affect all six tau isoforms. In contrast, mutations in exon 10 (N279K, ∆K280, L284L, P301L, P301S and S305N) only affect tau isoforms with four microtubule-binding repeats (Fig. 1a). Most missense mutations reduce the ability of tau to interact with microtubules, as reflected by a marked reduction in the ability of mutant tau to promote microtubule assembly. Moreover, several missense mutations stimulate the in vitro assembly of tau into filaments. Intronic mutations are located at positions 3, 12, 13, 14 and 16 of the intron following exon 10, with the first nucleotide of the splice-donor site taken as 1 (Fig. 1b) (Hutton et al., 1998; Spillantini et al., 1998; Yasuda et al.,