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Decreased synthesis of ribosomal proteins in tauopathy revealed by non‐canonical amino acid labelling

Evans, Harrison Tudor et al.

The EMBO journal. Volume 38:Number 13 (2019, July); pp n/a-n/a -- WILEY-VCH Verlag GmbH & Co. KGaA

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  • Title:
    Decreased synthesis of ribosomal proteins in tauopathy revealed by non‐canonical amino acid labelling
  • Author: Evans, Harrison Tudor;
    Benetatos, Joseph;
    van Roijen, Marloes;
    Bodea, Liviu‐Gabriel;
    Götz, Jürgen
  • Found In: The EMBO journal. Volume 38:Number 13 (2019, July); pp n/a-n/a
  • Journal Title: The EMBO journal
  • Subjects: Molecular biology--Periodicals; neurodegenerative disease--non‐canonical amino acid labelling--protein synthesis--ribosomal proteins--tauopathy; Dewey: 572.805
  • Rights: Licensed
  • Publication Details: WILEY-VCH Verlag GmbH & Co. KGaA
  • Abstract: Abstract:

    Tau is a scaffolding protein that serves multiple cellular functions that are perturbed in neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). We have recently shown that amyloid‐β, the second hallmark ofAD, inducesde novoprotein synthesis of tau. Importantly, this activation was found to be tau‐dependent, raising the question of whetherFTD‐tau by itself affects protein synthesis. We therefore applied non‐canonical amino acid labelling to visualise and identify newly synthesised proteins in the K369I tau transgenic K3 mouse model ofFTD. This revealed massively decreased protein synthesis in neurons containing pathologically phosphorylated tau, a finding confirmed in P301L mutant tau transgenicrTg4510 mice. Using quantitativeSWATHMSproteomics, we identified changes in 247 proteins of thede novoproteome of K3 mice. These included decreased synthesis of the ribosomal proteinsRPL23, RPLP0, RPL19 andRPS16, a finding that was validated in both K3 andrTg4510 mice. Together, our findings present a potential pathomechanism by which pathological tau interferes with cellular functions through the dysregulation of ribosomal protein synthesis.

    Synopsis:

    We demonstrate that protein synthesis is significantly decreased in the presence of frontotemporal dementia tau. UsingSWATHMSde novoproteomics we reveal altered synthesis of distinct sets of proteins, including ribosomal proteins.

    Global protein synthesis is decreased in transgenic mouse models of tauopathy and this decrease correlates with tau pathology.SWATHMSde novoproteomics shows that distinct clusters of proteins are altered in synthesis in mice with pathological tau.Ribosomal protein synthesis is decreased in two mouse models of tauopathy and this decrease is more pronounced as disease progresses.Total abundance of the ribosomal subunitRPl23 is decreased in mouse models of tauopathy and in humanFTD‐brain.

    Analyses of brain samples from transgenic mice and human patients reveal that pathogenic tau altersde novoprotein synthesis, suggesting a new mechanism underlying neurodegenerative disease pathology.


  • Identifier: System Number: ETOCvdc_100084331946.0x000001; Journal ISSN: 0261-4189; 10.15252/embj.2018101174
  • Publication Date: 2019
  • Physical Description: Electronic
  • Shelfmark(s): 3733.085000
  • UIN: ETOCvdc_100084331946.0x000001

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