Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery

Topic: Brain proteins, microglia and lab models

TDP-43 is a highly conserved and ubiquitously expressed member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family of proteins. Recently, TDP-43 was shown to be a major disease protein in the ubiquitinated inclusions characteristic of most cases of amyotrophic lateral sclerosis (ALS), tau-negative frontotemporal lobar degeneration (FTLD), and inclusion body myopathy. In these diseases, TDP-43 is redistributed from its predominantly nuclear location to ubiquitin-positive, cytoplasmic foci. The extent to which TDP-43 drives pathophysiology is unknown, but the identification of mutations in TDP-43 in familial forms of ALS and FTLD-U suggests an important role for this protein in pathogenesis. Little is known about TDP-43 function and only a few TDP-43 interacting proteins have been previously identified, which makes further insight into both the normal and pathological functions of TDP-43 difficult. Here we show, via a global proteomic approach, that TDP-43 has extensive interaction with proteins that regulate RNA metabolism. Some interactions with TDP-43 were found to be dependent on RNA-binding, whereas other interactions are RNA-independent. Disease-causing mutations in TDP-43 (A315T and M337V) do not alter its interaction profile. TDP-43 interacting proteins largely cluster into two distinct interaction networks, a nuclear/splicing cluster and a cytoplasmic/translation cluster, strongly suggesting that TDP-43 has multiple roles in RNA metabolism and functions in both the nucleus and the cytoplasm. Finally, we found numerous TDP-43 interactors that are known components of stress granules, and indeed, we find that TDP-43 is also recruited to stress granules.

@article{freibaum2010-20020773,
  author  = {Freibaum, B. D. and Chitta, R. K. and High, A. A. and Taylor, J. P.},
  title   = {{Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery}},
  journal = {Journal of proteome research},
  year    = {2010},
  doi     = {10.1021/pr901076y},
  pmid    = {20020773},
  url     = {https://doi.org/10.1021/pr901076y}
}

Key findings

• TDP-43 interacting proteins largely cluster into two distinct interaction networks, a nuclear/splicing cluster and a cytoplasmic/translation cluster, strongly suggesting that TDP-43 has multiple roles in RNA metabolism and functions in both the nucleus and the cytoplasm.
• Finally, we found numerous TDP-43 interactors that are known components of stress granules, and indeed, we find that TDP-43 is also recruited to stress granules.

Why it matters

This laboratory study found that TDP-43 interacts with many proteins involved in RNA metabolism, clustering into nuclear/splicing and cytoplasmic/translation networks, and that it is recruited to stress granules. It does not test any treatment or show a way to cure or prevent Alzheimer's disease.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1021/pr901076y
• PubMed: 20020773
• Original source →
• Free full text: PubMed Central →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

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