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Trends in Understanding the Pathological Roles of TDP-43 and FUS Proteins

Part of the Advances in Experimental Medicine and Biology book series (AEMB,volume 1281)

Abstract

Following the discovery of TDP-43 and FUS involvement in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD), the major challenge in the field has been to understand their physiological functions, both in normal and disease conditions. The hope is that this knowledge will improve our understanding of disease and lead to the development of effective therapeutic options. Initially, the focus has been directed at characterizing the role of these proteins in the control of RNA metabolism, because the main function of TDP-43 and FUS is to bind coding and noncoding RNAs to regulate their life cycle within cells. As a result, we now have an in-depth picture of the alterations that occur in RNA metabolism following their aggregation in various ALS/FTLD models and, to a somewhat lesser extent, in patients’ brains. In parallel, progress has been made with regard to understanding how aggregation of these proteins occurs in neurons, how it can spread in different brain regions, and how these changes affect various metabolic cellular pathways to result in neuronal death. The aim of this chapter will be to provide a general overview of the trending topics in TDP-43 and FUS investigations and to highlight what might represent the most promising avenues of research in the years to come.

Keywords

  • RNA binding proteins
  • TDP-43
  • FUS/TLS
  • ALS
  • FTLD
  • Neurodegeneration
  • Protein aggregation

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Fig. 1
Fig. 2

Abbreviations

ALS:

Amyotrophic lateral sclerosis

FTLD:

Frontotemporal lobar dementia

FUS/TLS:

Fused in sarcoma/translocated in liposarcoma

hnRNP:

Heterogeneous ribonucleoproteins

lncRNA:

Long noncoding RNA

mRNA:

Messenger RNA

miRNA:

MicroRNA

TDP-43:

TAR DNA binding protein 43 kDa

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Acknowledgments

This work was supported by AriSLA (Italy) grant (PathensTDP) and Beneficentia Stiftung (Liechtenstein).

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Buratti, E. (2021). Trends in Understanding the Pathological Roles of TDP-43 and FUS Proteins. In: Ghetti, B., Buratti, E., Boeve, B., Rademakers, R. (eds) Frontotemporal Dementias . Advances in Experimental Medicine and Biology, vol 1281. Springer, Cham. https://doi.org/10.1007/978-3-030-51140-1_15

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