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

Abstract

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 noncoding 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.

Cajal bodies in neurons

“…Mutations in the RNA binding proteins FUS and TDP-43, involved in transcription and mRNA splicing and transport, are responsible for a subset of ALS cases. 82 Interestingly, the number of Gems -identified with a single immunostaining for SMNdecreased in fibroblasts and mouse motor neurons depleted of FUS or TDP-43, suggesting a possible role of these bodies in ALS pathophysiology. [83][84][85] In the spinal cord of ALS mouse models, uridylate-rich (U) snRNAs belonging to minor spliceosome, which carries out U12-dependent splicing, are markedly reduced, as occurs in SMA.…”

Mice with endogenous TDP ‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

“…TDP‐43 is a ubiquitously expressed, predominantly nuclear, RNA binding protein, which is involved in multiple steps of RNA processing and maturation, including transcription and splicing (Ratti & Buratti, 2016; Ederle & Dormann, 2017). TDP‐43 has two RNA binding domains (RRM1 and RRM2) and a C‐terminal low complexity glycine‐rich domain (LCD), in which mutations causative for amyotrophic lateral sclerosis (ALS) are clustered (Ratti & Buratti, 2016; Ederle & Dormann, 2017).…”

“…TDP‐43 has two RNA binding domains (RRM1 and RRM2) and a C‐terminal low complexity glycine‐rich domain (LCD), in which mutations causative for amyotrophic lateral sclerosis (ALS) are clustered (Ratti & Buratti, 2016; Ederle & Dormann, 2017). …”

Neuronal cytoplasmic inclusions in tau, TDP-43, and FUS molecular subtypes of frontotemporal lobar degeneration share similar spatial patterns

“…Hence, a more localised pattern of cortical degeneration appears to be present in FTLD-TDP and FTLD-FUS. Compared with tau, which is widespread in neurons and important in the assembly and stabilisation of microtubules [27,51], both TDP-43 and FUS have more specific roles, TDP-43 in mRNA function, DNA repair, and in non-coding RNA metabolism [45] while FUS is important in regulating gene expression including transcription, splicing, and RNA transport [31]. In both TDP-43 and FUS, nuclear clearance results in the immediate aggregation in the cytoplasm of cells [33].…”