Journal
SCIENCE
Volume 349, Issue 6248, Pages 650-655Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aab0983
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Funding
- Robert Packard Center for ALS Research, Muscular Dystrophy Association
- Amyotrophic Lateral Sclerosis Association
- Target ALS
- Johns Hopkins University Neuropathology Pelda fund
- Johns Hopkins Alzheimer's Disease Research Center [NIH P50AG05146]
- Samuel I. Newhouse Foundation
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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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