C13621: Suppression of Non-conserved Cryptic Exons is Compromised in Human Neurodegenerative Diseases
Abstract
A novel mechanism underlying the suppression of non conserved cryptic exons. This mechanism is essential to maintain intron integrity, and is compromised in ALS-FTD, indicating that loss of function underlies pathogenesis of disease. Publication 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.
US Patent application filed claiming priority to PCT application published as WO 2016/205615.