Abstract
The intricate regulatory landscape of the central nervous system is increasingly understood to depend on the complex interplay between long non-coding RNAs (lncRNAs) and RNA-binding proteins (RBPs). Dysregulation of these interactions is a hallmark of neurodegenerative diseases, including Parkinson’s disease and Amyotrophic Lateral Sclerosis. This study employs an integrated approach, combining individual-nucleotide resolution UV cross-linking and immunoprecipitation (iCLIP) with comprehensive transcriptome profiling to map the lncRNA-protein interaction (LPI) networks in human-derived neurodegenerative models. By utilizing a revised iCLIP-seq protocol, we achieved high-resolution mapping of RBP binding sites across the lncRNA landscape. Our integrated analysis identified 142 hub lncRNAs that exhibit differential expression and altered binding patterns in diseased states. Notably, we observed a significant enrichment of interactions involving proteins associated with the spliceosome and proteostasis machinery. We demonstrate that specific lncRNAs act as molecular scaffolds, modulating the recruitment of RBPs to detained introns, a process recently implicated as a 'molecular brake' in neurodegeneration. Furthermore, our network analysis reveals that lncRNA-mediated sequestration of aggregation-prone proteins significantly influences cellular survival. These findings provide a high-resolution map of the ribofactor-lncRNA interactome, offering novel insights into the molecular mechanisms of neural decay and identifying potential therapeutic targets for stabilizing RNA-protein homeostasis in the aging brain.