Tau gene mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)

Abstract

Tau is a microtubule-associated protein that binds to microtubules and promotes microtubule assembly. Six tau isoforms are produced in adult human brain by alternative mRNA splicing from a single gene. Inclusion of a 31-amino acid repeat encoded by exon 10 of the tau gene gives rise to the three isoforms with four microtubule-binding repeats each. The other three tau isoforms have three repeats each. Abundant neurofibrillary lesions made of tau protein constitute a defining neuropathological characteristic of Alzheimer's disease. Filamentous tau protein deposits are also the defining characteristic of other neurodegenerative diseases, many of which are frontotemporal dementias or movement disorders, such as Pick's disease, progressive supranuclear palsy and corticobasal degeneration. It is well established that the distribution of tau pathology correlates with the presence of symptoms of disease. However, until recently, there was no genetic evidence linking dysfunction of tau protein to neurodegeneration. This has now changed with the discovery of more than 15 mutations in the tau gene in "frontotemporal dementia and parkinsonism linked to chromosome 17" (FTDP-17). Clinically, this condition is characterised by profound personality changes, progressive dementia and extrapyramidal symptoms. Neuropathologically, all cases with tau mutations examined to date have shown an abundant filamentous tau pathology in brain cells. Pathological heterogeneity is determined to a large exte…