TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A

NYGC ALS Consortium

Research output: Contribution to journalArticlepeer-review

Abstract

Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia1–3, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-434,5. 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 conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.

Original languageEnglish
Pages (from-to)131-137
Number of pages7
JournalNature
Volume603
Issue number7899
DOIs
StatePublished - 3 Mar 2022

Funding

FundersFunder number
Cancer Research UK FC001002
Collaborative Center for X-linked Dystonia-ParkinsonismMR/S006508/1, MR/M008606/1
Lady Edith Wolfson Senior Non-Clinical Fellowship959-799
NIH National Institute of AgingR56-AG055824, U01-AG068880
Neurological Research Trust
UK Dementia Research Institute FoundationUKDRI-1005
National Institutes of HealthU54NS123743
National Institutes of Health
National Institute on AgingU01AG068880
National Institute on Aging
National Institute of Neurological Disorders and Stroke
BrightFocus Foundation
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Wellcome Trust
Horizon 2020 Framework Programme835300
Horizon 2020 Framework Programme
Masonic Charitable Foundation893-792
Masonic Charitable Foundation
UK Research and InnovationMR/T042184/1
UK Research and Innovation
Medical Research CouncilFC001002, MR/R005184/1
Medical Research Council
Alzheimer's SocietyT32 GM136577
Alzheimer's Society
Motor Neurone Disease Association
Rosetrees Trust
Wolfson Foundation
Alzheimer’s Research UK107116/Z/15/Z
Alzheimer’s Research UK
Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica
UCLH Biomedical Research Centre

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