Introduction

The discovery of mutations in the tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) (1-4) has demonstrated that tau dysfunction can result in neurodegeneration and has allowed researchers to generate transgenic models of the human tauopathies (5) (see Table 1 for summary). Transgenic models permit studies on the mechanisms of formation of filamentous tau lesions in neurons and glia as well as their role in neurodegeneration. They also serve as models to develop treatments for tauopathies.

The tau gene is subject to alternative splicing of three exons, which generates six tau isoforms (6,7) (Fig. 1). Additional heterogeneity is derived from posttranslational modifications of tau. Two exons in the amino half of the molecule (exon 2 and exon 3) and one exon in the microtubule-binding domain (exon 10) are alternatively spliced (8). Exon 2 is included (1N) or excluded (0N), whereas exon 3 is always coexpressed with exon 2 (2N). Exon 10 contains a conserved repeat domain that is also present in exons 9, 11, and 12. Inclusion of exon 10 generates tau with 4 repeats (4R), whereas exclusion generates tau with 3 repeats (3R). The various splice combinations of tau are thus abbreviated as follows: 0N3R, 0N4R, 1N3R, 1N4R, 2N3R, and 2N4R. Adult brain has all six isoforms, whereas fetal tau is composed of 3R tau (9).

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