TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD

Abstract

Cytoplasmic aggregation of TDP-43, accompanied by its nuclear clearance, is a key common pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, a limited understanding of this RNA-binding protein (RBP) impedes the clarification of pathogenic mechanisms underlying TDP-43 proteinopathy. In contrast to RBPs that regulate splicing of conserved exons, we found that TDP-43 repressed the splicing of nonconserved cryptic exons, maintaining intron integrity. When TDP-43 was depleted from mouse embryonic stem cells, these cryptic exons were spliced into messenger RNAs, often disrupting their translation and promoting nonsense-mediated decay. Moreover, enforced repression of cryptic exons prevented cell death in TDP-43–deficient cells. Furthermore, repression of cryptic exons was impaired in ALS-FTD cases, suggesting that this splicing defect could potentially underlie TDP-43 proteinopathy.

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

“…exons ( Fig. 1), and increased inclusion of such exons was found in post-mortem ALS/FTD individuals (Ling et al 2015) to the potential detriment of cell survival (Tan et al 2016). While this result presents an important observable metric of TDP-43 LOF in disease, such cryptic exons are not exclusively regulated by TDP-43 and are bound by a number of other RBPs whose concentrations may vary in patients (Humphrey et al 2017).…”

“…Loss of TDP-43 function due to nuclear clearance can lead to particular splicing signatures of disease (Polymenidou et al 2011;Xiao et al 2011;Ling et al 2015) or to defective transport of distally targeted mRNAs (Ishiguro et al 2016). Intriguingly, it has been postulated that an important function of TDP-43 is the repression of cryptic Figure 2.…”

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

“…Remarkably, the skipping of constitutive exons induced by GOF is in contrast to the previously identified TDP‐43 LOF‐induced cryptic exons, which are normally repressed but in LOF are aberrantly included in mRNAs (Ling et al , 2015; Humphrey et al , 2017). …”

Heat Shock-induced Phosphorylation of TAR DNA-binding Protein 43 (TDP-43) by MAPK/ERK Kinase Regulates TDP-43 Function

“…TDP-43 regulates hundreds of genes through different RNA processing mechanisms, in particular through the regulation of splicing (18,19,22). TDP-43 cellular localization is highly dynamic and defects in nuclear import are linked to aggregation and neurotoxicity (9,38,39).…”

“…Although TDP-43 participates in different mechanisms of RNA processing and RNA transport, the regulation of splicing is its best-characterized function (20,21). In addition, recent findings show that TDP-43 plays a more global role in gene regulation as an inhibitor of cryptic exon inclusion (22).…”