Brain, Vol. 123, No. 5, 857-859,
May 2000
© 2000 Oxford University Press
Editorial |
Tau mutations in familial frontotemporal dementia
Brain Repair Centre and Department of Neurology, University of Cambridge Cambridge, UK MRC Laboratory of Molecular Biology, Cambridge, UK
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.
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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., 2000). Functionally, they lead to increased splicing-in of exon 10, resulting in a changed ratio of three-repeat to four-repeat tau isoforms, with a net overproduction of four-repeat tau. Overproduction of four-repeat tau is thus sufficient to lead to a filamentous tau pathology, resulting in neurodegeneration and dementia. The intronic mutations are believed to destabilize an RNA stem–loop structure located at the exon 10-intron boundary (Fig. 1b). In addition, the +3 mutation is predicted to lead to increased binding of U1 snRNA to the 5' splice site. The determination of the three-dimensional structure of this tau exon 10 splicing regulatory element RNA has shown that it consists of an upper and a lower stem that are separated by a bulging A, with an apical loop of six nucleotides (Fig. 1b) (Varani et al., 1999). Known mutations are located in the upper stem.
The emerging picture is one of coding region mutations that lead to a reduced ability of tau to interact with microtubules and of intronic mutations whose primary effects are at the RNA level, resulting in the overproduction of four-repeat tau. However, two missense mutations in exon 10 (N279K and S305N) deviate from this in that they do not lead to a reduced ability of tau to interact with microtubules. Instead, they increase splicing-in of exon 10, like the intronic mutations (D'Souza et al., 1999; Hasegawa et al., 1999). The N279K mutation creates a splice-enhancer sequence, which explains its effects (Clark et al., 1998). Similarly, the L284L mutation disrupts a splice-silencer sequence, resulting in increased splicing-in of exon 10 (D'Souza et al., 1999). This work has uncovered the existence of sequence elements regulating the alternative splicing of exon 10 within exon 10 itself. The S305N mutation (AGT to AAT) changes the last amino acid in exon 10 (Iijima et al., 1999). This sequence forms part of the stem-loop structure, where the mutation produces a destabilizing G to A transition at position –1 (Fig. 1b). Like the +3 mutation, the –1 mutation is also expected to lead to increased binding of U1 snRNA.
Stanford and colleagues describe a novel mutation in codon 305 (AGT to AGC) that is silent at the amino acid level (S305S) (Stanford et al., 2000). However, the T to C transition at position 0 disrupts the stem-loop structure, without a predicted effect on U1 snRNA binding (Fig. 1b). By exon trapping, it produced increased splicing-in of exon 10, as has previously been shown for the other six mutations that disrupt the stem–loop structure. Fixed brain tissue from an individual with the S305S mutation was used for neuropathological analysis. It showed an abundant tau pathology in nerve cells and glial cells, with the presence of straight and twisted filaments by electron microscopy. A neuronal and glial tau pathology has previously been found in all cases with mutations in exon 10 or in the intron following exon 10 (Spillantini et al., 2000). The lack of unfixed brain tissue from the patient with the S305S mutation precluded further analysis. It therefore remains to be seen whether isolated filaments are wide twisted ribbons made of four-repeat tau, as in cases with the +3, +12 and +16 mutations. It also remains to be determined whether soluble four-repeat tau is overexpressed, as has been shown for the +3, +12, +14 and +16 mutations.
Unlike most tau mutations, the S305S mutation produced only mild frontotemporal atrophy. Instead, basal ganglia, subthalamic nucleus and several midbrain regions were found to be severely affected. The distribution of tau pathology, as well as its cellular distribution, were reminiscent of PSP. The same was true of the clinical picture, with early postural instability and supranuclear vertical gaze palsy. The tau gene has recently been implicated in the aetiology of PSP, by virtue of the association of an intronic polymorphic dinucleotide marker and an extended haplotype with the disease (Conrad et al., 1997; Baker et al., 1999).
Although the S305S mutation led to a clinical and neuropathological picture resembling PSP in one individual, it produced a clinical picture of pre-senile dementia in two other individuals from the same family. This underscores the previously noted variability in clinical expression resulting from a given mutation in tau (Bugiani et al., 1999). So far, tau mutations have been shown to give rise to the clinical picture of frontotemporal dementia, AD, PD, PSP, CBD or progressive subcortical gliosis. The factors determining these different clinical phenotypes remain to be discovered. Meanwhile, the new work has firmly established the pivotal role that tau protein plays in a large number of neurodegenerative diseases.
References
Baker M, Litvan I, Houlden H, Adamson J, Dickson D, Perez-Tur J, et al. Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 1999; 8: 711–5.
Bugiani O, Murrell JR, Giaccone G, Hasegawa M, Ghigo G, Tabaton M, et al. Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol 1999; 58: 667–77.[Web of Science][Medline]
Clark LN, Poorkaj P, Wszolek Z, Geschwind DH, Nasreddine ZS, Miller B, et al. Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. Proc Natl Acad Sci USA 1998; 95: 13103–7.
Conrad C, Andreadis A, Trojanowski JQ, Dickson DW, Kang D, Chen X, et al. Genetic evidence for the involvement of tau in progressive supranuclear palsy. Ann Neurol 1997; 41: 277–81.[Web of Science][Medline]
D'Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM-Y, Bird T, et al. Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc Natl Acad Sci USA 1999; 96: 5598–603.
Hasegawa M, Smith MJ, Iijima M, Tabira T, Goedert M. FTDP-17 mutations N279K and S305N in tau produce increased splicing of exon 10. FEBS Lett 1999; 443: 93–6.[Web of Science][Medline]
Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998; 393: 702–5.[Medline]
Iijima M, Tabira T, Poorkaj P, Schellenberg GD, Trojanowski JQ, Lee VM-Y, et al. A distinct familial presenile dementia with a novel missense mutation in the tau gene. Neuroreport 1999; 10: 497–501.[Web of Science][Medline]
Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 1998; 43: 815–825.[Web of Science][Medline]
Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci USA 1998; 95: 7737–41.
Spillantini MG, Van Swieten JC, Goedert M. Tau gene mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Neurogenetics 2000; 2: 193–205.[Web of Science][Medline]
Stanford PM, Halliday GM, Brooks WS, Kwok JBJ, Storey CE, Creasey H, et al. Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene. Expansion of the disease phenotype caused by tau gene mutations. Brain 2000; 123: 880–93.
Varani L, Hasegawa M, Spillantini MG, Smith MJ, Murrell JR, Ghetti B, et al. Structure of tau exon 10 splicing regulatory element RNA and destabilization by mutations of frontotemporal dementia and parkinsonism linked to chromosome 17. Proc Natl Acad Sci USA 1999; 96: 8229–34.
Yasuda M, Takamatsu J, D'Souza I, Crowther RA, Kawamata T, Hasegawa M, et al. A novel mutation at position +12 in the intron following exon 10 of the tau gene in familial frontotemporal dementia (FTD-Kumamoto). Ann Neurol. In press 2000.
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