TDP-43 and other hnRNPs regulate cryptic exon inclusion of a key ALS/FTD risk gene, UNC13A.
PLoS Biol
; 21(3): e3002028, 2023 03.
Article
in En
| MEDLINE
| ID: mdl-36930682
ABSTRACT
A major function of TAR DNA-binding protein-43 (TDP-43) is to repress the inclusion of cryptic exons during RNA splicing. One of these cryptic exons is in UNC13A, a genetic risk factor for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The accumulation of cryptic UNC13A in disease is heightened by the presence of a risk haplotype located within the cryptic exon itself. Here, we revealed that TDP-43 extreme N-terminus is important to repress UNC13A cryptic exon inclusion. Further, we found hnRNP L, hnRNP A1, and hnRNP A2B1 bind UNC13A RNA and repress cryptic exon inclusion, independently of TDP-43. Finally, higher levels of hnRNP L protein associate with lower burden of UNC13A cryptic RNA in ALS/FTD brains. Our findings suggest that while TDP-43 is the main repressor of UNC13A cryptic exon inclusion, other hnRNPs contribute to its regulation and may potentially function as disease modifiers.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Heterogeneous-Nuclear Ribonucleoprotein L
/
Frontotemporal Dementia
/
Amyotrophic Lateral Sclerosis
Type of study:
Etiology_studies
/
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
PLoS Biol
Journal subject:
BIOLOGIA
Year:
2023
Type:
Article
Affiliation country:
United States