Loss of TDP-43 function drives cryptic circular RNAs in neurodegenerative diseases.

Authors

Chengzhang Zhu, Zhiyan Zhao, Bojun Song, Yan-Ming Chen, Yu Xiao, Zhe Zhang, Yingzhi Ye, Niannian Xu, Ruijia Zhang, Yongxin Huang, Juan C Troncoso, Chuan He, Shuying Sun

Published in

bioRxiv : the preprint server for biology. Sep 20, 2026. Epub Sep 20, 2026.

Abstract

TAR DNA-binding protein 43 (TDP-43) is a key pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and a critical regulator of RNA splicing. While loss of TDP-43 induces aberrant splicing in linear transcripts, its impact on circular RNA (circRNA) biogenesis remains unexplored. Here, we show that TDP-43 depletion in human neurons induces widespread circRNA changes, especially upregulation of a distinct class of cryptic circRNAs that arise specifically upon loss of TDP-43. Some of these cryptic circRNAs incorporate cryptic exons derived from intronic sequences. Notably, these cryptic circRNAs exhibit greater stability than their corresponding linear RNA isoforms and accumulate progressively in neurons. Moreover, cryptic circRNAs are elevated in postmortem brain tissues from ALS, FTD and Alzheimer's disease (AD) patients. These findings reveal a previously unrecognized role for TDP-43 in repressing cryptic circRNA formation and establish these circRNAs as stable molecular signatures of TDP-43 dysfunction.

PMID:
42780048
Bibliographic data and abstract were imported from PubMed on 24 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.