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

Neurogenetics. 2000 Mar;2(4):193-205. doi: 10.1007/pl00022972.


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 extent by the location of mutations in tau. Known mutations are either coding region or intronic mutations located close to the splice-donor site of the intron following exon 10. Most coding region mutations produce a reduced ability of tau to interact with microtubules, thus probably setting in motion the mechanisms that lead to the formation of tau filaments. Several of these mutations also promote sulphated glycosaminoglycan-induced assembly of tau into filaments. Intronic mutations and some coding region mutations produce increased splicing in of exon 10, resulting in an overexpression of four-repeat tau isoforms. Thus, a normal ratio of three-repeat to four-repeat tau isoforms is essential for preventing the development of tau pathology. Taken together, the new work has shown that dysfunction of tau protein causes neurodegeneration and dementia.

Publication types

  • Review

MeSH terms

  • Adult
  • Alternative Splicing
  • Brain / metabolism
  • Brain / pathology*
  • Chromosome Mapping
  • Chromosomes, Human, Pair 17*
  • Dementia / genetics*
  • Dementia / pathology
  • Humans
  • Microtubule-Associated Proteins / genetics*
  • Parkinsonian Disorders / genetics*
  • Parkinsonian Disorders / pathology
  • Protein Isoforms / genetics
  • tau Proteins / genetics*
  • tau Proteins / ultrastructure


  • MAPT protein, human
  • Microtubule-Associated Proteins
  • Protein Isoforms
  • tau Proteins