TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative diseases with clinical and pathological overlap. Landmark discoveries of mutations in the transactive response DNA-binding protein (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS) as causative of ALS and FTLD, combined with the abnormal aggregation of these proteins, have initiated a shifting paradigm for the underlying pathogenesis of multiple neurodegenerative diseases. TDP-43 and FUS/TLS are both RNA/DNA-binding proteins with striking structural and functional similarities. Their association with ALS and other neurodegenerative diseases is redirecting research efforts toward understanding the role of RNA processing regulation in neurodegeneration.

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

“…The increased vulnerability of mutant TDP-43 to calpain is in agreement with the fact that most ALS-linked point mutations in the TARDBP gene are localized to the C-terminal region 1,30,31 . In addition, the CTFs of mutant TDP-43 exhibit much faster kinetics of fibril formation than the CTFs of wildtype TDP-43 (ref.…”

“…As most of the ALS-linked point mutations in the TARDBP gene are localized to the C terminus 30,31 , we investigated the kinetic differences between the calpain-dependent cleavage of ALSlinked mutant TDP-43 and wild-type TDP-43. We found that calpain-I digested recombinant ALS-linked TDP-43 A315T and TDP-43 M337V faster than wild-type TDP-43 in vitro (Fig.…”

“…7c,d). The physiologically higher calpain activity in the ventral horns of the spinal cord may explain why mutations in the TARDBP gene cause ALS but not FTLD-TDP in affected patients [8][9][10]30,31 . Our studies of mutant TDP-43 imply that the same neuropathological changes may arise from different molecular mechanisms, that is, protease activation and increased vulnerability of the substrate to the protease.…”

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

“…Over 35 mutations have been described in FUS, which has been identified as the primary cause of ALS type 6 (Vance et al, 2009). In healthy controls this multifunctional protein, with roles ranging from DNA repair, transcriptional regulation and mRNA transport (Lagier‐Tourenne, Polymenidou, & Cleveland, 2010), is located primarily in the nucleus (Dormann et al, 2010); however, post mortem tissues of FUS‐ALS patients reveal cytoplasmic inclusions in affected neurons and glia (Kwiatkowski et al, 2009). Specifically, carriers of the FUS R521C, R521G, R521H, R524W, or G507N mutations show wide‐spread FUS pathology (Blair et al, 2009; Hewitt et al, 2010; Rademakers et al, 2010), including glial and neuronal cell loss, with increasing distribution of FUS‐immunoreactive inclusions in patients with longer disease durations (Suzuki et al, 2012).…”

RNA-binding proteins in neurological diseases

“…TDP-43 also contains a Q/N-rich prion-like element that mediates its interaction with polyQ aggregates. The biological function of TDP-43 is multi-faceted, including transcriptional regu-lation and post-transcriptional regulation at the different stages such as pre-mRNA splicing, microRNA biogenesis, RNA stability and RNA transport [131]. Here, we briefly discuss the role of TDP-43 in pre-mRNA splicing and mRNA stability control.…”