TDP-43 regulates its mRNA levels through a negative feedback loop

Authors

  • Youhna M Ayala,

    1. Department of Molecular Pathology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
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    • These authors contributed equally to this work
  • Laura De Conti,

    1. Department of Molecular Pathology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
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    • These authors contributed equally to this work
  • S Eréndira Avendaño-Vázquez,

    1. Department of Molecular Pathology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
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    • These authors contributed equally to this work
  • Ashish Dhir,

    1. Department of Molecular Pathology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
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    • These authors contributed equally to this work
  • Maurizio Romano,

    1. Department of Molecular Pathology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
    2. Department of Life Sciences, University of Trieste, Trieste, Italy
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  • Andrea D'Ambrogio,

    1. Department of Molecular Pathology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
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    • Present address: Program in Molecular Medicine, University of Massachusetts Medical School Worcester, MA 01605, USA
  • James Tollervey,

    1. MRC-Laboratory of Molecular Biology, Cambridge, UK
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  • Jernej Ule,

    1. MRC-Laboratory of Molecular Biology, Cambridge, UK
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  • Marco Baralle,

    1. Department of Molecular Pathology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
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  • Emanuele Buratti,

    1. Department of Molecular Pathology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
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  • Francisco E Baralle

    Corresponding author
    1. Department of Molecular Pathology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
    • Corresponding author. Department of Molecular Pathology, International Centre for Genetic Engineering and Biotechnology, Padriciano 99, Trieste 34149, Italy. Tel.: +39 040 375 7337; Fax: +39 040 375 7361; E-mail: baralle@icgeb.org

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Abstract

TAR DNA-binding protein (TDP-43) is an evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) involved in RNA processing, whose abnormal cellular distribution and post-translational modification are key markers of certain neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We generated human cell lines expressing tagged forms of wild-type and mutant TDP-43 and observed that TDP-43 controls its own expression through a negative feedback loop. The RNA-binding properties of TDP-43 are essential for the autoregulatory activity through binding to 3′ UTR sequences in its own mRNA. Our analysis indicated that the C-terminal region of TDP-43, which mediates TDP-43–hnRNP interactions, is also required for self-regulation. TDP-43 binding to its 3′ UTR does not significantly change the pre-mRNA splicing pattern but promotes RNA instability. Moreover, blocking exosome-mediated degradation partially recovers TDP-43 levels. Our findings demonstrate that cellular TDP-43 levels are under tight control and it is likely that disease-associated TDP-43 aggregates disrupt TDP-43 self-regulation, thus contributing to pathogenesis.

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