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

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.