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Amyotrophic lateral sclerosis-associated proteins TDP-43 and FUS/TLS function in a common biochemical complex to co-regulate HDAC6 mRNA.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that preferentially targets motor neurons. It was recently found that dominant mutations in two related RNA-binding proteins, TDP-43 (43-kDa TAR DNA-binding domain protein) and FUS/TLS (fused in sarcoma/translated in liposarcoma) cause a subset of ALS. The convergent ALS phenotypes associated with TDP-43 and FUS/TLS mutations are suggestive of a functional relationship; however, whether or not TDP-43 and FUS/TLS operate in common biochemical pathways is not known. Here we show that TDP-43 and FUS/TLS directly interact to form a complex at endogenous expression levels in mammalian cells. Binding was mediated by an unstructured TDP-43 C-terminal domain and occurred within the context of a 300-400-kDa complex that also contained C-terminal cleavage products of TDP-43 linked to neuropathology. TDP-43 C-terminal fragments were excluded from large molecular mass TDP-43 ribonucleoprotein complexes but retained FUS/TLS binding activity. The functional significance of TDP-43-FUS/TLS complexes was established by showing that RNAi silencing of either TDP-43 or FUS/TLS reduced the expression of histone deacetylase (HDAC) 6 mRNA. TDP-43 and FUS/TLS associated with HDAC6 mRNA in intact cells and in vitro, and competition experiments suggested that the proteins occupy overlapping binding sites. The combined findings demonstrate that TDP-43 and FUS/TLS form a functional complex in intact cells and suggest that convergent ALS phenotypes associated with TDP-43 and FUS/TLS mutations may reflect their participation in common biochemical processes.

Pubmed ID: 20720006

Authors

  • Kim SH
  • Shanware NP
  • Bowler MJ
  • Tibbetts RS

Journal

The Journal of biological chemistry

Publication Data

October 29, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: CA124722
  • Agency: NINDS NIH HHS, Id: NS059001

Mesh Terms

  • Amyotrophic Lateral Sclerosis
  • Cell Line
  • DNA-Binding Proteins
  • Gene Expression Regulation
  • HeLa Cells
  • Histone Deacetylases
  • Humans
  • Motor Neurons
  • Mutation
  • Phenotype
  • Protein Interaction Mapping
  • RNA Interference
  • RNA, Messenger
  • RNA-Binding Protein FUS
  • RNA-Binding Proteins