PANDORA-seq uncovers sensitive mitochondrial small RNA alterations associated with increased lysosome activity in an Alzheimer's Disease Mouse Model

Emerging small noncoding RNAs (sncRNAs), including tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs), are critical in diverse biological processes, such as neurological diseases. Traditional sncRNA-seq protocols often miss these sncRNAs due to their modifications. We have recently developed PANDORA-seq, a method enabling more comprehensive detection of modified sncRNAs by overcoming the RNA modifications. Using PANDORA-seq, we have revealed an updated sncRNA profile enriched by tsRNAs/rsRNAs in the mouse cortex and found a particularly significant downregulation of mitochondrial tsRNAs and rsRNAs in an Alzheimer's disease (AD) mouse model, compared to genomic tsRNAs and rsRNAs. Moreover, our integrated analysis of cortex gene expression and sncRNA profiles reveals that those downregulated mitochondrial sncRNAs are negatively correlated with enhanced lysosomal activity, suggesting a crucial interplay between mitochondrial RNA dynamics and lysosomal function in AD. Given the versatile tsRNA/tsRNA molecular actions in cellular regulation, our data provides insights for future mechanistic study of AD with potential therapeutic strategies. Overall design: Brain cortex tissue was collected from wild-type (WT) and Alzheimer's disease (AD) model mice, both with a C57BL/6J genetic background at 6 months of age. For each group, 8 biological replicates were analyzed using PANDORA-seq. In addition, traditional small non-coding RNA sequencing (sncRNA-seq) was performed with 7 replicates for the AD the WT group.