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

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

Research output: Contribution to journalArticlepeer-review


AU A major: Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly 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.

Original languageEnglish (US)
Article numbere3002028 e3002028
JournalPLoS biology
Issue number3 March
StatePublished - Mar 2023

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)


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