The UNC13A cryptic exon associates with cognitive impairment in Alzheimer's disease
More about Open Access at the CrickAuthors list
Madison M Reeves Sara Aviles Carpintero Matteo Zanovello Karen Jansen-West Mei Yue Anna Calliari Yuping Song Judith Dunmore Candela Maroto Cidfuentes Sophie Ball Jennifer M Kachergus Heather E Killeen Bailey Rawlinson Erica Engelberg-Cook Michael DeTure Gregory S Day Neill R Graff-Radford Bradley F Boeve David S Knopman Ronald C Petersen Melissa Murray Aubrey E Thompson Dennis W Dickson Pietro Fratta Leonard Petrucelli Keith A Josephs Mercedes Prudencio
Toggle all authors (27)
Abstract
BACKGROUND: TAR DNA-binding protein of 43 kDa (TDP-43) is often found in the brains of patients with Alzheimer's disease (AD), where it co-occurs with amyloid β plaques and tau neurofibrillary tangles, and associates with accelerated cognitive decline and brain atrophy. TDP-43's function of repressing the inclusion of cryptic exons (CEs) during RNA splicing is compromised in AD. A single-nucleotide polymorphism (SNP) located within the CE in the UNC13A gene [rs12973192 (C > G)] is associated with higher disease risk and reduced survival in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) by weakening TDP-43 binding promoting CE inclusion. OBJECTIVE: To investigate the influence of the rs12973192 UNC13A CE SNP and UNC13A cryptic splicing on TDP-43 pathology, survival and cognitive impairment in AD. METHODS: We evaluated the UNC13A CE SNP in a cohort of 1,672 AD, including 643 AD brains with available cognitive measurements and 73 AD cases for which we measured cryptic RNA levels in the amygdala. We also evaluated a cohort of 466,517 from the UK Biobank to determine associations between the UNC13A CE SNP and dementia diagnosis. RESULTS: In AD, the UNC13A CE SNP associated significantly with cognitive decline, but not with TDP-43 pathology or with survival. UNC13A cryptic RNA levels in the amygdala were a better predictor of cognitive decline than the UNC13A CE SNP itself, while STMN2-another well-known CE target-exhibited no such association. CONCLUSIONS: These findings point to UNC13A cryptic splicing as a specific driver of cognitive decline in AD, outperforming both genetic risk and other cryptic targets.
Journal details
Journal
Alzheimer's Research and Therapy
Volume
18
Pages
187
Available online
Publication date
Full text links
Publisher website (DOI)
10.1186/s13195-026-02157-7
Europe PubMed Central
42596024
Pubmed
42596024
Keywords
Related topics
Type of publication
