Missense and Splice Site Mutations in Tau Associated with FTDP-17 Multiple Pathogenic Mechanisms
The recent identification of mutations in the gene encoding the microtubule associated protein Tau in the inherited dementia FTDP-17 has demonstrated that Tau dysfunction can lead to neurodegeneration. At least nine missense mutations and one deletion mutation (ΔK280) have been identified in exons 9 through 13 that encode the microtubule binding domain of Tau. In addition, six different mutations have been found in the 5′ splice site of exon 10. The FTDP-17 missense and splice site mutations have been demonstrated to have multiple effects on the biology and function of Tau. It is likely that they result in the varied set of clinical and neuropathological features observed in the FTDP-17 tauopathies.
The majority of missense mutations have been demonstrated in vitro to partially inhibit the direct binding of Tau to microtubules and Tau-induced polymerization of tubulin. In addition, altered Tau self-interaction leading to increased filament formation has been shown in vitro for the P301L, V337M and R406W mutations, suggesting that at least two properties of Tau may be disturbed by the conformation change induced by the majority of FTDP-17 tau missense mutations.
Mutations in the 5′ splice site of exon 10 (-2, +3, +12, +13, +14, +16) all destabilize a stem-loop structures that regulates alternative splicing of this exon. This presumably results in increased binding of splicing factors that are crucial to the early stages of spliceosome formation (most likely the U1 snRNP). As a result, increased levels of exon 10+ RNA and thus Tau isoforms with 4 microtubule binding repeats are generated. The presence of mutations that affect the alternative splicing of exon 10 demonstrates that the ratio of isoforms with 4 and 3 microtubule binding repeats is crucial to Tau function. The N279K mutation is unusual in that it is a missense mutation that does not affect the interaction of Tau with microtubules but increases splicing of exon 10, likely through the strengthening of a splice enhancer element.
In general, the common link between the missense and splice site tau mutations is that each is likely to increase the level of unbound Tau in the cell, either all six isoforms or 4 repeat isoforms specifically. This increase in unbound Tau may lead to the formation of polymerized Tau filaments and insoluble inclusions, resulting in neurodegeneration. Alternatively, disrupted microtubule function may underlie the pathogenic mechanism in FTDP-17.
KeywordsSplice Site Progressive Supranuclear Palsy Splice Site Mutation Microtubule Binding Microtubule Binding Domain
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