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

Iovino, Mariangela; Pfisterer, Ulrich LU ; Holton, Janice L.; Lashley, Tammaryn; Swingler, Robert J.; Calo, Laura; Treacy, Rebecca; Revesz, Tamas; Parmar, Malin LU and Goedert, Michel, et al. (2014) In Acta Neuropathologica 127(2). p.283-295
Abstract
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... (More)
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. (Less)
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publication status
published
subject
keywords
K298E MAPT mutation, Tauopathies, Human induced-neurons
in
Acta Neuropathologica
volume
127
issue
2
pages
283 - 295
publisher
Springer
external identifiers
  • wos:000329993100010
  • scopus:84896733978
ISSN
1432-0533
DOI
10.1007/s00401-013-1219-1
language
English
LU publication?
yes
id
a1fc4284-02b7-47b7-a4ec-712325388072 (old id 4318852)
date added to LUP
2014-03-03 07:59:54
date last changed
2017-11-19 04:01:08
@article{a1fc4284-02b7-47b7-a4ec-712325388072,
  abstract     = {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.},
  author       = {Iovino, Mariangela and Pfisterer, Ulrich and Holton, Janice L. and Lashley, Tammaryn and Swingler, Robert J. and Calo, Laura and Treacy, Rebecca and Revesz, Tamas and Parmar, Malin and Goedert, Michel and Muqit, Miratul M. K. and Spillantini, Maria Grazia},
  issn         = {1432-0533},
  keyword      = {K298E MAPT mutation,Tauopathies,Human induced-neurons},
  language     = {eng},
  number       = {2},
  pages        = {283--295},
  publisher    = {Springer},
  series       = {Acta Neuropathologica},
  title        = {The novel MAPT mutation K298E: mechanisms of mutant tau toxicity, brain pathology and tau expression in induced fibroblast-derived neurons},
  url          = {http://dx.doi.org/10.1007/s00401-013-1219-1},
  volume       = {127},
  year         = {2014},
}