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.

Figure 1.

TDP-43 and FUS/TLS mutations in ALS and FTLD patients. Thirty-eight dominant mutations have been identified in TDP-43 in sporadic and familial ALS patients and in rare FTLD patients, with most lying in the C-terminal glycine-rich region. All are missense mutations, except for the truncating mutation TDP-43^Y374X (upper panel). Thirty mutations have been identified in FUS/TLS in familial and sporadic ALS cases and in rare FTLD patients (R514S and G515S were found in cis). Most mutations are clustered in the last 17 amino acids and in the glycine-rich region (lower panel). NLS, nuclear localization signal; NES, nuclear export signal. Domains have been defined according to http://www.uniprot.org and http://www.cbs.dtu.dk/services/NetNES.

Figure 2.

Proposed physiological roles of TDP-43 and FUS/TLS. (A) Summary of major steps in RNA processing from transcription to translation or degradation. (B) TDP-43 binds single-stranded TG-rich elements in promoter regions thereby blocking transcription of the downstream gene [shown for TAR DNA of HIV (38) and mouse SP-10 gene (132,150)]. (C) FUS/TLS associates with TBP within the TFIID complex suggesting that it participates in the general transcriptional machinery (–159). (D) In response to DNA damage, FUS/TLS is recruited in the promoter region of cyclin D1 (CCND1) by sense and antisense non-coding RNAs (ncRNAs) and represses CCND1 transcription (145). (E) TDP-43 binds a UG track in intronic regions preceding alternatively spliced exons and enhances their exclusion [shown for CFTR (38,40,96,130,131,160) and apolipoprotein A-II (161)]. (F) FUS/TLS was identified as a part of the spliceosome (–170) and (G) was shown to promote exon inclusion in H-ras mRNA, through indirect binding to structural regulatory elements located on the downstream intron (177). (H) Both proteins were found in a complex with Drosha, suggesting that they may be involved in miRNA processing (183). (I) Both TDP-43 and FUS/TLS shuttle between the nucleus and the cytosol (134,142) and (J) are incorporated in SGs where they form complexes with mRNAs and other RNA binding proteins (,,,–204). (K) TDP-43 and FUS/TLS are both involved in the transport of mRNAs to dendritic spines and/or the axonal terminal where they may facilitate local translation (–189,191). Examples of such cargo transcripts are the low molecular weight NFL for TDP-43 (51,208) and the actin-stabilizing protein Nd1-L for FUS/TLS (147).