Mutations causing neurodegenerative tauopathies

Biochim Biophys Acta. 2005 Jan 3;1739(2-3):240-50. doi: 10.1016/j.bbadis.2004.08.007.


Tau is the major component of the intracellular filamentous deposits that define a number of neurodegenerative diseases. They include the largely sporadic Alzheimer's disease (AD), 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 tau dysfunction. This was resolved when mutations in Tau were found to cause FTDP-17. Currently, 32 different mutations have been identified in over 100 families. About half of the known mutations have their primary effect at the protein level. 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 and perturb the normal ratio of three-repeat to four-repeat tau isoforms. Where studied, this resulted in a relative overproduction of tau protein with four microtubule-binding domains in the brain. Individual 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. At a practical level, the new work is leading to the production of experimental animal models that reproduce the essential molecular and cellular features of the human tauopathies, including the formation of abundant filaments made of hyperphosphorylated tau protein and nerve cell degeneration.

Publication types

  • Review

MeSH terms

  • Alzheimer Disease / genetics*
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins / genetics
  • Mutation*
  • Nerve Degeneration
  • Neurodegenerative Diseases / genetics
  • Tauopathies / genetics*
  • tau Proteins / genetics*


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