NON-CODING RNA PROFILING IN SERUM, CSF, OLFACTORY MUCOSA, TEARS AND SKIN IDENTIFIES NOVEL MOLECULAR SIGNATURES IN AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEMENTIA

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are considered two manifestations of a shared neurodegenerative disease continuum, characterized by the overlapping of clinical, genetic, and pathological features. These disorders can co-occur in the same patient; however, the molecular mechanisms driving ALS, FTD, or their mixed phenotypes remain incompletely understood. Moreover, reliable biomarkers for the clinical diagnosis of ALS/FTD are still lacking. In this context, non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), represent promising biomarkers, given their key role in post-transcriptional gene regulation and their potential for molecular stratification of ALS and FTD. The aim of this study was to identify novel biomarkers not only in CSF, but also in easily accessible tissues, including skin, olfactory mucosa, serum, and tears, capable of discriminating ALS/FTD clinical phenotypes and unveiling specific biological mechanisms involved in the diseases. The enrolled patients were 12 ALS, 12 FTD and 12 subjects affected by non-neurodegenerative conditions as controls. Non-coding RNA profiling was performed by qPCR using microfluidic TaqMan Array Cards to analyze 754 miRNAs and 96 growth factor–related lncRNAs across multiple tissues and biological fluids. Bioinformatic analyses assessed differential expression and multimodal data integration, tailored to sample size. Our integrated molecular data revealed distinct non-coding RNA fingerprints across the ALS/FTD disease spectrum associated to proliferation, neurodegeneration and neuroinflammation. These signatures hold promise as reliable biomarkers to improve early diagnostic accuracy and may also represent potential therapeutic targets, providing new insights into the molecular mechanisms underlying neurodegeneration and supporting their translational relevance.