TGF-beta 1 enhances neurite outgrowth via regulation of proteasome function and EFABP

Neurobiol Dis. 2010 Jun;38(3):395-404. doi: 10.1016/j.nbd.2010.02.011. Epub 2010 Mar 6.


Malfunction of the ubiquitin-proteasome system has been implicated as a causal factor in the pathogenesis of aggregation-related disorders, e.g. Parkinson's disease. We show here that Transforming growth factor-beta 1 (TGF-beta), a multifunctional cytokine and trophic factor for dopaminergic (DAergic) neurons modulates proteasome function in primary midbrain neurons. TGF-beta differentially inhibited proteasomal subactivities with a most pronounced time-dependent inhibition of the peptidyl-glutamyl peptide hydrolyzing-like and chymotrypsin-like subactivity. Regulation of proteasomal activity could be specifically quantified in the DAergic subpopulation. Protein blot analysis revealed an accumulation of ubiquitinated proteins after TGF-beta treatment. The identity of these enriched proteins was further analyzed by 2D-gel electrophoresis and mass spectrometry. We found epidermal fatty acid binding protein (EFABP) to be strongly increased and ubiquitinated after TGF-beta treatment and confirmed this finding by co-immunoprecipitation. While application of TGF-beta increased neurite regeneration in a scratch lesion model, downregulation of EFABP by siRNA significantly decreased this effect. We thus postulate that a differential regulation of proteasomal function, as demonstrated for TGF-beta, can result in an enrichment of proteins, such as EFABP, that mediate physiological functions, such as neurite regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Enlargement
  • Cells, Cultured
  • Dopamine / metabolism
  • Eye Proteins / metabolism*
  • Fatty Acid-Binding Proteins / metabolism*
  • Hydrolysis
  • Mesencephalon / physiology
  • Nerve Regeneration / physiology
  • Nerve Tissue Proteins / metabolism*
  • Neurites / physiology*
  • Neurons / physiology
  • Proteasome Endopeptidase Complex / physiology*
  • Rats
  • Rats, Wistar
  • Time Factors
  • Transforming Growth Factor beta1 / metabolism*
  • Ubiquitination


  • Eye Proteins
  • Fabp5 protein, rat
  • Fatty Acid-Binding Proteins
  • Nerve Tissue Proteins
  • Transforming Growth Factor beta1
  • Proteasome Endopeptidase Complex
  • Dopamine