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

Abstract

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