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The novel MAPT mutation K298E: mechanisms of mutant tau toxicity, brain pathology and tau expression in induced fibroblast-derived neurons

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Author

  • Mariangela Iovino
  • Ulrich Pfisterer
  • Janice L. Holton
  • Tammaryn Lashley
  • Robert J. Swingler
  • Laura Calo
  • Rebecca Treacy
  • Tamas Revesz
  • Malin Parmar
  • Michel Goedert
  • Miratul M. K. Muqit
  • Maria Grazia Spillantini
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Summary, in English

Frontotemporal lobar degeneration (FTLD) consists of a group of neurodegenerative diseases characterized by behavioural and executive impairment, language disorders and motor dysfunction. About 20-30 % of cases are inherited in a dominant manner. Mutations in the microtubule-associated protein tau gene (MAPT) cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T). Here we report a novel MAPT mutation (K298E) in exon 10 in a patient with FTDP-17T. Neuropathological studies of post-mortem brain showed widespread neuronal loss and gliosis and abundant deposition of hyperphosphorylated tau in neurons and glia. Molecular studies demonstrated that the K298E mutation affects both protein function and alternative mRNA splicing. Fibroblasts from a skin biopsy of the proband taken at post-mortem were directly induced into neurons (iNs) and expressed both 3-repeat and 4-repeat tau isoforms. As well as contributing new knowledge on MAPT mutations in FTDP-17T, this is the first example of the successful generation of iNs from skin cells retrieved post-mortem.

Publishing year

2014

Language

English

Pages

283-295

Publication/Series

Acta Neuropathologica

Volume

127

Issue

2

Document type

Journal article

Publisher

Springer

Topic

  • Neurosciences

Keywords

  • K298E MAPT mutation
  • Tauopathies
  • Human induced-neurons

Status

Published

Research group

  • Neurobiology

ISBN/ISSN/Other

  • ISSN: 1432-0533