Review: transactive response DNA-binding protein 43 (TDP-43): mechanisms of neurodegeneration

Abstract

Since the identification of phosphorylated and truncated transactive response DNA-binding protein 43 (TDP-43) as a primary component of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions, and the discovery that mutations in the TDP-43 gene cause ALS, much effort has been directed towards establishing how TDP-43 contributes to the development of neurodegeneration. Although few in vivo models are presently available, findings thus far strongly support the involvement of abnormally modified TDP-43 in promoting TDP-43 aggregation and cellular mislocalization. Therefore, TDP-43-mediated neurotoxicity is likely to result from a combination of toxic gains of function conferred by TDP-43 inclusions as well as from the loss of normal TDP-43 function. Nonetheless, the exact neurotoxic TDP-43 species remain unclear, as do the mechanism(s) by which they cause neuronal death. Moreover, little is currently known about the roles of TDP-43, both in the nucleus and the cytoplasm, making it difficult to truly appreciate the detrimental consequences of aberrant TDP-43 function. This review will summarize what is currently understood regarding normal TDP-43 function and the involvement of TDP-43 in neurodegeneration, and will also highlight some of the many remaining questions in need of further investigation.

Figure 1

A schematic representation of the gene encoding transactive response DNA-binding protein 43 (TDP-43) and full-length TDP-43 protein. The human TARDBP gene is located on chromosome 1p36 and contains 5 coding and 2 noncoding exons (panel B) [32]. Coding regions are shown in yellow while noncoding regions are gray. Identified mutations in exons 3, 4 and 6 of TARDBP are shown using the numbering of the 414-amino acid full-length isoform of TDP-43 (panel A). Mutations observed in familial and sporadic ALS are indicated in blue and black, respectively. Mutations in red have been reported for both familial and sporadic ALS. The A90V mutation is shown in gray as this mutation has been observed in both affected and control individuals [28,31,110]. Panel C depicts the protein structure of full-length human TDP-43. Note the two RNA recognition motifs (RRM1, RRM2), the nuclear localization signal (NLS), the nuclear export signal (NES) and the glycine (Gly)-rich domain. Caspase cleavages sites of TDP-43 are indicated in panel D [55], as are the proteolytic sites identified in brain tissue from FTLD-U patients [86,87]. In panel E, TDP-43 sites reportedly phosphorylated in FTLD-U and ALS are shown [100]. Note that these sites are all present in the C-terminus of TDP-43.