Tau mutations in familial frontotemporal dementia.

Abstract

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 three- and 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 …