Trends in Molecular Medicine
ReviewTau gene mutations: dissecting the pathogenesis of FTDP-17
Section snippets
Tau mutations
The vast majority of tau mutations are missense, deletion or silent mutations in the coding region, or mutations located close to the splice-donor site of the intron that follows the alternatively spliced exon 10 (Fig. 2a). Most coding-region mutations are located in (exons 9–12) or near (exon 13) the MT-binding region, although two mutations in exon 1 of tau (R5H and R5L) have recently been reported 18., 19.. Mutations in exon 1 (R5H and R5L), exon 9 (K257T, L266V and G272V), exon 11 (S320F),
Neuropathology of FTDP-17
To date, all analysed cases of FTDP-17 have been characterized by the presence of an abundant filamentous pathology, consisting of hyperphosphorylated tau protein. However, the morphology, isoform composition, and distribution of tau filaments and deposits appear to vary according to the type of mutation (Fig. 3 and Table 1).
Missense mutations located outside exon 10, which primarily reduce MT assembly, lead to a tau pathology that is largely neuronal, without a significant glial component.
Clinical phenotypes and FTDP-17
Different tau mutations lead to specific tau pathologies (although variation mainly in the distribution of pathology has been reported for the +16 mutation [63]). By contrast, the ensuing clinical phenotypes appear to be more variable. Indeed, clinical presentation can differ not only between mutations, but also within a single mutation and even within individual families. For example, clinical variability has been reported in nine UK families carrying the +16 mutation [64]. Similarly, for the
Tau genotype and tauopathies
The causative role of tau gene mutations in FTDP-17 has been proved. Furthermore, there is also evidence supporting an association of the tau gene with other tauopathies, such as PSP and CBD. This idea resulted initially from the discovery of a polymorphic dinucleotide repeat in the intron between exons 9 and 10 of the tau gene that is over-represented in PSP patients, suggesting that it might be a risk factor for the disease [74]. The association was later confirmed in Caucasians, but not in
Conclusions
The discovery of mutations in the tau gene that lead to tau aggregation and FTDP-17 demonstrates that tau dysfunction can lead to neurodegenerative disease. The question of how a mutation in the tau gene leads to neurodegeneration is, as yet, unanswered. The primary effect of most missense mutations appears to be a reduced ability of tau to interact with MTs. This might equate to a partial loss of function, resulting in MT destabilization and deficits in cellular processes, such as axonal
References (95)
Microtubule organization and dynamics dependent on microtubule-associated proteins
Curr. Opin. Cell Biol.
(1994)Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2
Brain Res.
(1986)Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease
Neuron
(1989)- et al.
Tau protein pathology in neurodegenerative diseases
Trends Neurosci.
(1998) Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau
Am. J. Pathol.
(1998)Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly
FEBS Lett.
(1998)High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands
Am. J. Hum. Genet.
(1999)Accelerated filament formation from tau protein with specific FTDP-17 missense mutations
FEBS Lett.
(1999)Effects of frontotemporal dementia FTDP-17 mutations on heparin-induced assembly of tau filaments
FEBS Lett.
(1999)Mutations in tau reduce its microtubule binding properties in intact cells and affect its phosphorylation
FEBS Lett.
(1999)