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Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly

M Hasegawa1, M J Smith, M Goedert

  • 1Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.

FEBS Letters
|November 21, 1998
PubMed

Insights

Missense mutations in the tau gene reduce its ability to assemble microtubules. This loss-of-function may explain familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is associated with mutations in the tau gene.
  • Intronic mutations in tau lead to an abnormal increase in four-repeat tau isoforms.
  • The impact of exonic tau mutations on protein function remains largely unknown.

Purpose of the Study:

  • To investigate the functional consequences of known exonic missense mutations in the tau gene.
  • To determine if these mutations affect the tau protein's ability to promote microtubule assembly.

Main Methods:

  • Site-directed mutagenesis was used to introduce specific tau mutations (G272V, P301L, V337M, R406W).
  • In vitro assays were performed to assess the ability of mutated tau proteins to promote microtubule assembly.

Main Results:

  • The G272V, P301L, V337M, and R406W tau mutations significantly reduced the protein's capacity to promote microtubule assembly.
  • This indicates a partial loss-of-function for these specific tau variants.

Conclusions:

  • The studied missense mutations in the tau gene impair its microtubule-binding and assembly-promoting functions.
  • This partial loss-of-function is a potential primary mechanism underlying FTDP-17 in patients with these tau mutations.

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