TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD

Nuclear depletion of TDP-43 is a defining pathological feature of ALS and FTD and drives widespread RNA misprocessing, including cryptic exon formation. This study set out to determine whether TDP-43 also controls circular RNA biogenesis and whether its dysfunction creates disease-specific circRNA species.

The authors identified TDP-43 as a regulator of circRNA biogenesis in multiple human neuronal cell models. Loss of normal TDP-43 function induced the de novo formation of cryptic circular RNAs (c-circRNAs). Analysis of post-mortem brain transcriptomic data then found a subset of c-circRNAs that were specific to ALS and FTD cases with TDP-43 pathology.

They developed highly sensitive rolling-circle amplification-based circRNA detection assays that could distinguish TDP-43 pathology in human CNS tissues with a 0.99 AUC. c-circRNAs were also found to co-occur with cryptic linear splicing events, revealing complex RNA misprocessing hotspots associated with loss of disease-relevant proteins including RPTOR and EHMT1.

Notably, one c-circRNA originates from UNC13A, a gene whose cryptic exon has been linked to a major ALS/FTD GWAS hit and is being pursued as a therapeutic target using splice-switching antisense oligonucleotides. The authors showed that c-circUNC13A is co-regulated with the linear cryptic transcript, and that suppressing the UNC13A cryptic exon reduces c-circUNC13A in cultured neurons and in vivo, supporting its potential as a target-engagement biomarker for emerging UNC13A-directed therapies. Overall, the work identifies a novel molecular mechanism for TDP-43 dysfunction and opens avenues for understanding ALS/FTD pathogenesis and developing much-needed pathology biomarkers.