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

Mariaangela 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 (Lead / Corresponding author), Maria Grazia Spillantini (Lead / Corresponding author)

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    Abstract

    Frontotemporal lobar degeneration (FTLD) is the one of the most frequent neurodegenerative disorders characterized by behavioral and executive impairment, language disorders and motor dysfunction. Hereditary forms of FTLD are frequently reported and about 20-30% of cases exhibit an autosomal dominant transmission. Microtubule associate protein tau (MAPT) gene mutations are associated with early onset FTLD. Here we have identified a new MAPT mutation on exon 10 that alters both the protein function and the RNA alternative splicing. Biochemical and neuropathological studies indicate a high pathogenicity of this new MAPT mutation. Moreover induced neurons transdifferentiated from patient skin-derived fibroblasts and carrying the new MAPT mutation express both 3R and 4R tau isoforms differently from those obtained from embryonic fibroblasts which express only 3R tau isoform indicating that they are not mature neurons.
    Original languageEnglish
    Pages (from-to)283-295
    JournalActa Neuropathologica
    Volume127
    Issue number2
    DOIs
    Publication statusPublished - Feb 2014

    Keywords

    • K298E MAPT mutation
    • Tauopathies
    • Human induced-neurons

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    Iovino, M., Pfisterer, U., Holton, J. L., Lashley, T., Swingler, R. J., Calo, L., Treacy, R., Revesz, T., Parmar, M., Goedert, M., Muqit, M. M. K., & Spillantini, M. G. (2014). The novel MAPT mutation K298E: mechanisms of mutant tau toxicity, brain pathology and tau expression in induced fibroblast-derived neurons. Acta Neuropathologica, 127(2), 283-295. https://doi.org/10.1007/s00401-013-1219-1