TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A
National Hospital for Neurology and Neurosurgery · University College London · +67 more institutions
Abstract
Abstract Variants of UNC13A , a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia 1–3 , two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43 4,5 . Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A , resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these…
Citation impact
- FWCI
- 56.07
- Percentile
- 100%
- References
- 67
Authors
98- 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
- MJMatthew J. Keuss
National Hospital for Neurology and Neurosurgery, University College London
- SESarah E. Hill
National Institute of Neurological Disorders and Stroke
- MZMatteo Zanovello
National Hospital for Neurology and Neurosurgery, University College London
Topics & keywords
- Amyotrophic lateral sclerosis
- Frontotemporal dementia
- Single-nucleotide polymorphism
- RNA splicing
- Synapse
- C9orf72
- Gene
- Dementia
Funding
- BFBrightFocus Foundation
- WTWellcome TrustAwards: FC001002, 107116/Z/15/Z, /Z/15/Z
- URUK Research and InnovationAward: MR/T042184/1
- CRCancer Research UKAward: FC001002
- NINational Institute for Health and Care Research
- MNMotor Neurone Disease AssociationAward: MR/M008606/1
- ECEuropean CommissionAward: 835300
- RTRosetrees Trust
- WFWolfson Foundation
- EEisai
- UCUniversity College London Hospitals NHS Foundation Trust
- UDUK Dementia Research InstituteAward: UKDRI-1005
- NINational Institutes of HealthAwards: U01-AG068880, U54NS123743, GM136577, NIH T32, T32 GM136577, R56-AG055824
- MRMedical Research CouncilAwards: MR/R005184/1, MR/K018523/1, MR/S006508/1, MR/T042184/1, MR/S006508/1, MR/R005184/1, MC_EX_MR/N501931/1, MR/M008606/1, MR/W005190/1, MR/M008606/1, FC001002, MC_PC_MR/S022708/1
- NINational Institute of Child Health and Human Development
- EKEunice Kennedy Shriver National Institute of Child Health and Human Development
- RPRobert Packard Center for ALS Research, Johns Hopkins University