Yuka Koike, Sarah Pickles, Virginia Estades Ayuso, Karen Jansen-West, Yue A Qi, Ziyi Li, Lillian M Daughrity, Mei Yue, Yong-Jie Zhang, Casey N Cook, Dennis W Dickson, Michael Ward, Leonard Petrucelli, Mercedes Prudencio
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...
March 17, 2023: PLoS Biology