TDP-43 and other hnRNPs regulate cryptic exon inclusion of a key ALS/FTD risk gene, UNC13A.

Autor: Koike, Yuka, Pickles, Sarah, Estades Ayuso, Virginia, Jansen-West, Karen, Qi, Yue A., Li, Ziyi, Daughrity, Lillian M., Yue, Mei, Zhang, Yong-Jie, Cook, Casey N., Dickson, Dennis W., Ward, Michael, Petrucelli, Leonard, Prudencio, Mercedes
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Zdroj: PLoS Biology; 3/17/2023, Vol. 21 Issue 3, p1-24, 24p, 1 Diagram, 5 Graphs
Abstrakt: 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. This study shows that TDP-43 is the most important repressor of cryptic exon splicing in UNC13A, a risk factor for amyotrophic lateral sclerosis and frontotemporal dementia. While TDP-43 is the main repressor of UNC13A cryptic exon inclusion, other hnRNPs contribute to its regulation and may potentially act as disease modifiers. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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