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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)277-88
Number of pages12
JournalEMBO Journal
Volume30
Issue number2
DOIs
Publication statusPublished - 19 Jan 2011

Keywords

  • Base Sequence
  • Blotting, Northern
  • Cell Line
  • DNA-Binding Proteins/genetics
  • Feedback, Physiological/physiology
  • Gene Expression Regulation/genetics
  • Gene Library
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Molecular Sequence Data
  • Plasmids/genetics
  • Polymerase Chain Reaction
  • RNA Interference
  • RNA Processing, Post-Transcriptional/genetics
  • RNA, Messenger/metabolism
  • Sequence Analysis, DNA

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