Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins

J Neurochem. 2016 Aug;138 Suppl 1:95-111. doi: 10.1111/jnc.13625. Epub 2016 Jun 15.


The multiple roles played by RNA binding proteins in neurodegeneration have become apparent following the discovery of TAR DNA binding protein 43 kDa (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS) involvement in amyotrophic lateral sclerosis and frontotemporal lobar dementia. In these two diseases, the majority of patients display the presence of aggregated forms of one of these proteins in their brains. The study of their functional properties currently represents a very promising target for developing the effective therapeutic options that are still lacking. This aim, however, must be preceded by an accurate evaluation of TDP-43 and FUS/TLS biological functions, both in physiological and disease conditions. Recent findings have uncovered several aspects of RNA metabolism that can be affected by misregulation of these two proteins. Progress has also been made in starting to understand how the aggregation of these proteins occurs and spreads from cell to cell. The aim of this review will be to provide a general overview of TDP-43 and FUS/TLS proteins and to highlight their physiological functions. At present, the emerging picture is that TDP-43 and FUS/TLS control several aspects of an mRNA's life, but they can also participate in DNA repair processes and in non-coding RNA metabolism. Although their regulatory activities are similar, they regulate mainly distinct RNA targets and show different pathogenetic mechanisms in amyotrophic lateral sclerosis/frontotemporal lobar dementia diseases. The identification of key events in these processes represents today the best chance of finding targetable options for therapeutic approaches that might actually make a difference at the clinical level. The two major RNA Binding Proteins involved in Amyotrophic Lateral Sclerosisi and Frontotemporal Dementia are TDP-43 and FUST/TLS. Both proteins are involved in regulating all aspects of RNA and RNA life cycle within neurons, from transcription, processing, and transport/stability to the formation of cytoplasmic and nuclear stress granules. For this reason, the aberrant aggregation of these factors during disease can impair multiple RNA metabolic pathways and eventually lead to neuronal death/inactivation. The purpose of this review is to provide an up-to-date perspective on what we know about this issue at the molecular level. This article is part of the Frontotemporal Dementia special issue.

Keywords: ALS; FTLD; FUS/TLS; RNA binding proteins; TDP-43; protein aggregation.

Publication types

  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / physiopathology
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / physiology*
  • Frontotemporal Dementia / genetics*
  • Frontotemporal Dementia / physiopathology
  • Frontotemporal Lobar Degeneration / metabolism
  • Humans
  • RNA-Binding Protein FUS / genetics*
  • RNA-Binding Protein FUS / physiology*
  • TDP-43 Proteinopathies / genetics*
  • TDP-43 Proteinopathies / pathology*


  • DNA-Binding Proteins
  • RNA-Binding Protein FUS
  • TARDBP protein, human