Mis-spliced transcripts generate de novo proteins in TDP-43–related ALS/FTD
National Institutes of Health · University of Oxford · +14 more institutions
Abstract
Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human…
Citation impact
- FWCI
- 54.78
- Percentile
- 100%
- References
- 74
Authors
51- SSSahba SeddighiCorresponding
National Institutes of Health, University of Oxford, National Institute of Neurological Disorders and Stroke
- YQYue QiCorresponding
National Institutes of Health, National Institute of Neurological Disorders and Stroke, National Institute on Aging
- ABAnna‐Leigh BrownCorresponding
National Hospital for Neurology and Neurosurgery, University College London
- OGOscar G. Wilkins
The Francis Crick Institute, National Hospital for Neurology and Neurosurgery, University College London
- CBColleen Bereda
National Institutes of Health, National Institute of Neurological Disorders and Stroke, National Institute on Aging
Topics & keywords
- Exon
- Biology
- Frontotemporal dementia
- Phenotype
- Transcriptome
- Gene
- Loss function
- Genetics
Funding
- AAAlzheimer's Association
- MDMuscular Dystrophy Association
- CACure Alzheimer's Fund
- WTWellcome TrustAwards: 102186/B/13/Z, CC0102, 102186
- FCFrancis Crick Institute
- TATarget ALS
- AGAustralian Government
- ASAlzheimer's Society
- CRCancer Research UKAward: CC0102
- MNMotor Neurone Disease AssociationAward: MR/M008606/1
- UDUK Dementia Research Institute
- NINational Institutes of HealthAwards: R35NS097273, U54NS123743, RF1AG062077, GM136577, T32 GM136577, P01NS084974, U19AG063911
- MRMedical Research CouncilAwards: MR/M023664/1, MR/S006508/1, MR/T046015/1, MR/S006508/1, MR/M008525/1, MR/J009482/1, CC0102, MR/W005190/1, MR/M008606/1, MC_PC_MR/S022708/1
- LLeibniz-Gemeinschaft
- NINational Institute of Neurological Disorders and StrokeAwards: R35NS097273, U54NS123743, P01NS084974
- RPRobert Packard Center for ALS Research, Johns Hopkins University