Tau gene mutations and their effects

Tau is the major component of the intracellular filamentous deposits that define a number of neurodegenerative diseases, including the largely sporadic Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and argyrophilic grain disease, as well as the inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). For a long time, it was unclear whether the dysfunction of tau protein follows disease or whether disease follows the dysfunction of tau protein. The identification of mutations in Tau as the cause of FTDP-17 has resolved this issue. About half of the known mutations have their primary effect at the protein level, and they reduce the ability of tau protein to interact with microtubules and increase its propensity to assemble into abnormal filaments. The other mutations have their primary effect at the RNA level, thus perturbing the normal ratio of three-repeat to four-repeat tau isoforms. Where studied, this resulted in the relative overproduction of tau protein with four microtubule-binding repeats in brain. Several Tau mutations give rise to diseases that resemble progressive supranuclear palsy, corticobasal degeneration, or Pick's disease. Moreover, the H1 haplotype of Tau has been identified as a significant risk factor for progressive supranuclear palsy and corticobasal degeneration.