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

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Science  07 Aug 2015:
Vol. 349, Issue 6248, pp. 650-655
DOI: 10.1126/science.aab0983

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Mechanistic surprise in ALS-FTD

Intense efforts have focused on identifying therapeutic targets for misfolded proteins that cause amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). Ling et al. show that the main culprit of proteinopathy, TDP-43, acts as a splicing suppressor of nonconserved cryptic exons. These exons often disrupt messenger RNA translation and promote nonsense-mediated decay. When TDP-43 was depleted in cells, a set of nonconserved cryptic exons spliced into target RNAs, leading to down-regulation of corresponding proteins critical for cellular function. Repression of cryptic exons prevented cell death in TDP-43–null cells. Because brains of ALS-FTD cases showed evidence of missplicing of cryptic exons, failure in these regions may underlie TDP-43 proteinopathy.

Science, this issue p. 650

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.

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