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

Youhna M Ayala, Laura De Conti, S Eréndira Avendaño‐Vázquez, Ashish Dhir, Maurizio Romano, Andrea D'Ambrogio, James Tollervey, Jernej Ule, Marco Baralle, Emanuele Buratti, Francisco E Baralle

Author Affiliations

  1. Youhna M Ayala1,,
  2. Laura De Conti1,,
  3. S Eréndira Avendaño‐Vázquez1,,
  4. Ashish Dhir1,,
  5. Maurizio Romano1,2,
  6. Andrea D'Ambrogio1,,
  7. James Tollervey3,
  8. Jernej Ule3,
  9. Marco Baralle1,
  10. Emanuele Buratti1 and
  11. Francisco E Baralle*,1
  1. 1 Department of Molecular Pathology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
  2. 2 Department of Life Sciences, University of Trieste, Trieste, Italy
  3. 3 MRC‐Laboratory of Molecular Biology, Cambridge, UK
  1. *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{at}icgeb.org
  1. These authors contributed equally to this work

  • Present address: Program in Molecular Medicine, University of Massachusetts Medical School Worcester, MA 01605, USA

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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.

  • Received April 29, 2010.
  • Accepted November 3, 2010.
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