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

Citations Over TimeTop 1% of 2022 papers

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.

Related Papers

• → C9orf72 repeat expansions that cause frontotemporal dementia are detectable among patients with psychosis(2015)25 cited
• → [ 18 F]AV‐1451 binding is increased in frontotemporal dementia due to C9orf72 expansion(2018)23 cited
• → Slowly progressive behavioral frontotemporal dementia with C9orf72 mutation. Case report and review of the literature(2018)18 cited
• Amyotrophic Lateral Sclerosis with Frontotemporal Dementia in the Presence of C9orf72 Repeat Expansion-A Case Report.(2016)
• → C9ORF72 and frontotemporal dementia: a systematic review and meta- analysis(2018)1 cited