TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor

Authors

  • I.-Fan Wang,

    1. Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
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    • 1

      The present address of I.-F. Wang is the Neuroscience Research Institute, University of California, Santa Barbara, CA 93106, USA.

  • Lien-Szn Wu,

    1. Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
    2. Institute of Genome Science, National Yang-Ming University, Shih-Pai, Taipei, Taiwan
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    • 2

      Both these authors contributed equally to this study.

  • Hsiang-Yu Chang,

    1. Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
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    • 2

      Both these authors contributed equally to this study.

  • C.-K. James Shen

    1. Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
    2. Institute of Genome Science, National Yang-Ming University, Shih-Pai, Taipei, Taiwan
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Address correspondence and reprint requests to C.-K. James Shen, Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 115, Taiwan. E-mail: ckshen@imb.sinica.edu.tw

Abstract

TDP-43, recently identified as a signature protein of the pathogenic inclusions in the brains cells of frontotemporal lobar degeneration patients, is a 43 kDa RNA-binding protein. It has been known mainly as a nuclear factor capable of repressing transcription and promoting exon exclusion. TDP-43 also forms distinct nuclear substructures linking different types of nuclear bodies. In this study, we provide the first evidence supporting TDP-43 as a neuronal activity-responsive factor in the dendrites of hippocampal neurons. In particular, TDP-43 resides in the somatodendrites mainly in the form of RNA granules colocalized with the post-synaptic protein PSD-95. These granules also contain RNAs including at least the β-actin mRNA and CaMKIIα mRNA. Furthermore, TDP-43 is localized in the dendritic processing (P) body and it behaves as a translational repressor in an in vitro assay. Related to this, repetitive stimuli by KCl greatly enhance the colocalization of TDP-43 granules with FMRP and Staufen 1, two RNA-binding proteins known to regulate mRNA transport and local translation in neurons. These data together suggest that TDP-43 is a neuronal activity-responsive factor functioning in the regulation of neuronal plasticity, the impairment of which would lead to the development of certain forms of neurodegenerative diseases including frontotemporal lobar degeneration.

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