Tau Function And Dysfunction

Tau belongs to a family of proteins known as microtubule-associated proteins (MAPs) (Weingarten et al., 1975). Involved in microtubule assembly and stabilization in neurons and probably glia, tau is important for the maintenance of the cytoskeleton (LoPresti et al., 1995). Although tau is normally localized mainly in the axons, where it plays a role in axonal motorprotein transport (Ebneth et al., 1998), somatodendritic localization of tau is thought to occur during tau dysfunction. This altered localization of tau is characteristic of pre-tangle and neurofibrillary tangle inclusions found in neurons and occasionally glia in certain neurodegenerative diseases. Neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein are key intracellular lesions in numerous neurodegenerative diseases including Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD).

Tau is regulated in part by alternative splicing of exons 2, 3, and 10 to generate six tau mRNAs encoding six different tau isoforms (3R0N, 3R1N, 3R2N, 4R0N, 4R1N, 4R2N) (Figure 8.1). Exons 2 and 3 encode N-terminal tau domains of uncertain function, whereas exon 10 encodes one of four microtubule-binding domains. Thus, alternative splicing of exon 10 gives rise to tau isoforms with 4 (exon 10 + ) or 3 (exon 10—) microtubule-binding repeats (4R and 3R tau, respectively). An approximate 1:1 ratio of 4R:3R tau protein normally exists in adult human brain as opposed to the near exclusive presence of 4R tau isoforms in the murine adult brain (Goedert et al., 1989; Kosik et al., 1989). Aggregation of different isoforms of tau results in NFTs composed of filaments with various morphologies. In AD, the NFTs are

Figure 8.1. Schematic of the tau gene, alternative splicing, and protein isoforms. (A) The tau gene is encoded on chromosome 17q21. Alternatively spliced exons 2, 3, and 10 are shown above the constitutive exons. Exons 4A, 6, and 8 are generally excluded from human tau mRNA. Most tau transcripts include the intron between exons 13 and 14. (B) Exons 2, 3, and 10 (shaded boxes) are alternatively spliced to yield six tau isoforms (3R0N, 3R1N, 3R2N, 4R0N, 4R1N, 4R2N). The microtubules-binding domains (black boxes) are encoded by exons 9-12

Figure 8.1. Schematic of the tau gene, alternative splicing, and protein isoforms. (A) The tau gene is encoded on chromosome 17q21. Alternatively spliced exons 2, 3, and 10 are shown above the constitutive exons. Exons 4A, 6, and 8 are generally excluded from human tau mRNA. Most tau transcripts include the intron between exons 13 and 14. (B) Exons 2, 3, and 10 (shaded boxes) are alternatively spliced to yield six tau isoforms (3R0N, 3R1N, 3R2N, 4R0N, 4R1N, 4R2N). The microtubules-binding domains (black boxes) are encoded by exons 9-12

largely composed of paired helical filaments composed of all six tau isoforms with a small number of straight filaments; however, in PSP straight tau filaments composed mainly of four repeat isoforms are the major component of the tau inclusions.

Tau MUTATIONS AND FTDP-17

The association of tau mutations with FTDP-17 provided the first direct evidence that tau dysfunction can lead to neurodegeneration (Hutton et al., 1998; Poorkaj et al., 1998; Spillantini et al., 1998b). Nearly 20 tau mutations have been associated with FTDP-17 (Figure 8.2). These mutations include both intronic and exonic mutations that disrupt the alternative splicing of tau exon 10 as well as missense mutations that alter the function of tau. Tau splicing mutations (i.e. S305N/S, N279K, exon 10 +3, +13, +14, +16) generally increase the ratio of tau isoforms containing four microtubule-binding domains to three microtubule-binding domains (Hutton et al., 1998; Spillantini et al., 1998b; Hasegawa et al., 1999; Stanford et al., 2000). However, one unique deletion mutation, DK280, has been shown to inhibit exon 10 splicing in vitro. The effect of this mutation (DK280) suggests that disruption of the normal 4R:3R ratio, rather than simply an increase in 4R tau, is sufficient for the development of FTDP-17. However, the effect of the

P301L/S

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