Neurodegeneration and Transposable Element–Driven Immune Responses in C9orf72-ALS/FTD

Neurodegenerative diseases with a dementia component, such as Alzheimer’s disease (AD) and C9orf72-associated ALS/FTD (C9-ALS/FTD), exhibit genomic instability and aberrant activation of transposable elements. Our previous work in AD uncovered a pathogenic mechanism whereby retrotransposon (RTE) mobilization generates RNA::DNA hybrids that trigger innate immunity through the cGAS–STING pathway. Here, we aim to determine whether this RTE-RNA::DNA hybrid-STING axis is also engaged in C9-ALS/FTD, and to determine its clinical relevance while assessing its potential as a therapeutic target using patient-derived cerebral organoids.

We employed a translational approach combining C9-ALS/FTD patients postmortem tissue with patient-derived cerebral organoids. In human brain tissue, activation of the RTE-RNA::DNA hybrid-STING axis was assessed using single-cell transcriptomic profiling, biochemical assays and immunofluorescence microscopy. Six-month-old cerebral organoids were validated as an in vitro model recapitulating the molecular signatures observed in patient tissue and subsequently used for pharmacological testing. Organoids were treated with the FDA-approved reverse transcriptase inhibitor lamivudine, and effects on RNA::DNA hybrid accumulation and downstream signaling were quantified.

In the frontal cortex of C9-ALS/FTD patients, we observed aberrant RTE activation, accompanied by cytoplasmic RNA::DNA hybrid accumulation and STING pathway activation. Organoids faithfully recapitulated these phenotypes. Treatment with lamivudine significantly reduced RNA::DNA hybrid accumulation, demonstrating pharmacological modulation of this pathway and supporting its therapeutic potential in C9-ALS/FTD.

This study provides the first demonstration that the RTE–RNA::DNA hybrid–STING axis is aberrantly activated in C9-ALS/FTD, linking retrotransposon dysregulation to disease-relevant innate immune signaling. By showing that RNA::DNA hybrid accumulation can be reduced with lamivudine, we highlight a translatable therapeutic entry point targeting this pathway in C9-ALS/FTD and related dementias.