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

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by nuclear depletion of TDP-43, which leads to widespread RNA misprocessing, including the formation of cryptic exons. Researchers have now discovered that TDP-43 dysfunction also induces the de novo formation of cryptic circular RNAs (c-circRNAs) in multiple human neuronal cell models.

By analyzing post-mortem brain transcriptomic data, they identified specific c-circRNAs linked to ALS and FTD cases with TDP-43 pathology. Their highly sensitive circRNA detection assays enabled them to distinguish TDP-43 pathology in human CNS tissues with a 0.99 AUC. Intriguingly, these c-circRNAs can co-occur with cryptic linear splicing events, revealing complex RNA misprocessing hotspots that result in loss of disease-relevant proteins like RPTOR and EHMT1.

One such c-circRNA originates from UNC13A, a gene previously associated with an ALS/FTD genetic risk factor and currently being explored as a therapeutic target using splice-switching antisense oligonucleotides (ASOs). The researchers found that c-circUNC13A is co-regulated with the linear cryptic transcript and that suppressing UNC13A cryptic exon reduces c-circUNC13A levels in cultured neurons and in vivo, making it a promising target engagement biomarker for upcoming UNC13A-directed therapies.

This groundbreaking work sheds light on a novel molecular mechanism behind TDP-43 dysfunction, offering new perspectives on disease pathogenesis and the urgent need for improved pathology biomarkers.