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Mutation in the tau gene in familial multiple system tauopathy with presenile dementia

M G Spillantini1, J R Murrell, M Goedert

  • 1Medical Research Council Centre for Brain Repair and Department of Neurology, University of Cambridge, Robinson Way, Cambridge CB2 2PY, UK. mgsll@cam.ac.uk

Proceedings of the National Academy of Sciences of the United States of America
|June 24, 1998
PubMed

Insights

A genetic mutation in the tau gene causes familial multiple system tauopathy with presenile dementia (MSTD). This leads to an abnormal ratio of tau protein isoforms, forming toxic tau filaments and causing neurodegeneration.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Familial multiple system tauopathy with presenile dementia (MSTD) is a neurodegenerative disease characterized by abundant tau protein pathology.
  • MSTD is classified under familial frontotemporal dementias with Parkinsonism linked to chromosome 17 (FTDP-17), a group of inherited dementias with an unknown genetic cause.

Purpose of the Study:

  • To identify the genetic basis of familial MSTD.
  • To investigate the role of tau protein isoforms in the pathogenesis of MSTD.

Main Methods:

  • Genetic analysis to identify mutations in the tau gene.
  • Biochemical analysis of tau protein isoforms in affected individuals.

Main Results:

  • A G to A transition mutation was identified in the intron following exon 10 of the microtubule-associated protein tau gene in familial MSTD patients.
  • This mutation disrupts a predicted stem-loop structure near the splice-donor site.
  • An abnormal increase in soluble tau protein isoforms with four microtubule-binding repeats compared to three-repeat isoforms was observed in familial MSTD.

Conclusions:

  • The identified mutation in the tau gene is the likely cause of familial MSTD.
  • A dysregulated ratio of tau isoforms, specifically a preponderance of four-repeat isoforms, leads to the formation of abnormal tau filaments.
  • These findings suggest that tau gene dysregulation can cause neurodegeneration and have implications for Alzheimer's disease and other tauopathies.

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