In:
PLOS Biology, Public Library of Science (PLoS), Vol. 21, No. 3 ( 2023-3-17), p. e3002028-
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.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3002028
DOI:
10.1371/journal.pbio.3002028.g001
DOI:
10.1371/journal.pbio.3002028.g002
DOI:
10.1371/journal.pbio.3002028.g003
DOI:
10.1371/journal.pbio.3002028.g004
DOI:
10.1371/journal.pbio.3002028.g005
DOI:
10.1371/journal.pbio.3002028.g006
DOI:
10.1371/journal.pbio.3002028.s001
DOI:
10.1371/journal.pbio.3002028.s002
DOI:
10.1371/journal.pbio.3002028.s003
DOI:
10.1371/journal.pbio.3002028.s004
DOI:
10.1371/journal.pbio.3002028.s005
DOI:
10.1371/journal.pbio.3002028.s006
DOI:
10.1371/journal.pbio.3002028.s007
DOI:
10.1371/journal.pbio.3002028.s008
DOI:
10.1371/journal.pbio.3002028.s009
DOI:
10.1371/journal.pbio.3002028.s010
DOI:
10.1371/journal.pbio.3002028.s011
DOI:
10.1371/journal.pbio.3002028.s012
DOI:
10.1371/journal.pbio.3002028.s013
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2126773-X