Hereditary frontotemporal dementia caused by Tau gene mutations

Abstract

Tau protein is involved in microtubule assembly and stabilization. Filamentous deposits made of tau constitute a defining characteristic of several neurodegenerative diseases. The relevance of tau dysfunction for neurodegeneration has been clarified through the identification of mutations in the Tau gene in cases with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Although the mechanisms by which these mutations lead to nerve cell death are only incompletely understood, it is clear that they cause the formation of tau filaments with distinct morphologies and isoform compositions. The range of tau pathology identified in FTDP-17 recapitulates that in sporadic tauopathies, indicating a major role for tau dysfunction in these diseases.

Figure 1

Schematic representation of the Tau gene and the six tau isoforms expressed in adult human brain. A. The human Tau gene contains 16 exons, of which exons 2, 3 and 10 (dark gray boxes) are alternatively spliced. Exons 4A, 6 and 8 (light gray boxes) are not transcribed in human brain. B. Six tau isoforms are generated by alternative mRNA splicing of exons 2, 3 and 10 (dark gray boxes). They range from 352 to 441 amino acids in length. The black boxes represent the microtubule‐binding repeats of tau.

Figure 2

Overview of Tau mutations identified in frontotemporal dementia and parkinsonism linked to chromosome 17. All known coding region mutations are located in exons 1, 9, 10, 11, 12 and 13. The alternatively spliced exon 10 is depicted in gray. Mutations are numbered according to the longest tau isoform (441 amino acids).

Figure 3

Magnetic resonance imaging. Moderate atrophy of the anterior temporal lobes in a patient with the P301L mutation in exon 10 of Tau.

Figure 4

Tau pathology in cases with the G272V and ΔK280 Tau mutations. Tau‐immunoreactive Pick bodies in the dentate gyrus of the hippocampus (A,C), the caudate nucleus (B) and the frontal cortex (D). Note the tau‐positive astrocyte (arrowed) in (D). (A,B), case with mutation G272V in exon 9 of Tau. (C,D), case with mutation ΔK280 in exon 10 of Tau.