Integrative multi-omics analyses reveal nuclear noncoding RNA-mediated regulatory landscape in Alzheimer's disease

Alzheimer's disease (AD) progression involves complex molecular mechanisms underlying neuronal dysfunction. While emerging evidence on long noncoding RNAs (lncRNAs) is accumulating, the relevance of nuclear noncoding RNAs (ncRNAs) to neurodegenerative diseases remains poorly understood. Small Cajal body-specific RNA 13 (scaRNA13) is a nuclear ncRNA implicated in RNA species regulation, which remains insufficiently characterized in neuronal systems and AD pathogenesis. Here, we performed integrative analyses of human postmortem brain transcriptomes and AD mouse models to examine scaRNA13 expression across disease stages, sex, and brain regions. RNA-seq and proteomic analyses were used to assess scaRNA13-associated changes in gene expression, splicing, and RNA-protein interactions. Functional assays in neuronal cells were conducted to evaluate the effects of scaRNA13 perturbation on RNA processing, protein synthesis, and tau-related pathology. scaRNA13 was aberrantly upregulated in AD patient brains with a pronounced elevation observed in female patients at advanced stages. Perturbation of scaRNA13 altered splicing patterns and global translational capacity, accompanied by altered tau aggregation- and phosphorylation-related phenotypes in neuronal cell systems. These findings support scaRNA13 as an AD-associated nuclear ncRNA candidate and suggest that scaRNA13 perturbation is associated with changes in RNA processing, translational regulation, and tau-related cellular phenotypes in neuronal cell systems.