Proteomic analyses reveal that loss of TDP-43 affects RNA processing and intracellular transport

Neuroscience. 2015 May 7;293:157-70. doi: 10.1016/j.neuroscience.2015.02.046. Epub 2015 Mar 2.


Transactive response DNA-binding protein 43 (TDP-43) is a predominantly nuclear, ubiquitously expressed RNA and DNA-binding protein. It recognizes and binds to UG repeats and is involved in pre-mRNA splicing, mRNA stability and microRNA metabolism. TDP-43 is essential in early embryonic development but accumulates in cytoplasmic aggregates in amyotrophic lateral sclerosis (ALS) and tau-negative frontotemporal lobar degeneration (FTLD). It is not known yet whether cytoplasmic aggregates of TDP-43 are toxic or protective but they are often associated with a loss of TDP-43 from the nucleus and neurodegeneration may be caused by a loss of normal TDP-43 function or a gain of toxic function. Here we present a proteomic study to analyze the effect of loss of TDP-43 on the proteome. MS data are available via ProteomeXchange with identifier PXD001668. Our results indicate that TDP-43 is an important regulator of RNA metabolism and intracellular transport. We show that Ran-binding protein 1 (RanBP1), DNA methyltransferase 3 alpha (Dnmt3a) and chromogranin B (CgB) are downregulated upon TDP-43 knockdown. Subsequently, transportin 1 level is increased as a result of RanBP1 depletion. Improper regulation of these proteins and the subsequent disruption of cellular processes may play a role in the pathogenesis of the TDP-43 proteinopathies ALS and FTLD.

Keywords: RanBP1; TDP-43; amyotrophic lateral sclerosis; comparative proteomics; frontotemporal lobar degeneration; intracellular transport.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Chromogranin B / metabolism
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methyltransferase 3A
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Nuclear Proteins / metabolism
  • Proteomics*
  • RNA / metabolism*
  • beta Karyopherins / metabolism


  • Carrier Proteins
  • Chromogranin B
  • DNA-Binding Proteins
  • DNMT3A protein, human
  • Nuclear Proteins
  • TARDBP protein, human
  • TNPO1 protein, human
  • beta Karyopherins
  • ran-binding protein 1
  • RNA
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A