Format

Send to

Choose Destination
Science. 2015 Aug 7;349(6248):650-5. doi: 10.1126/science.aab0983.

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

Author information

1
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.
2
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.
3
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. wong@jhmi.edu.

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.

PMID:
26250685
PMCID:
PMC4825810
DOI:
10.1126/science.aab0983
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center