RNA biomarkers in spinal muscular atrophy: enhancing pathogenesis understanding and guiding precision medicine

Fig. 1. Overall scheme of the hierarchical organization of biological samples and biomarker types that have been used in spinal muscular atrophy (SMA) research and clinical monitoring. CSF, cerebrospinal fluid. The molecular biomarkers fall into several categories, including mRNA-encoding SMN, specific miRNAs, and broader analyses, such as the complete miRNome profile. Further trends are towards more comprehensive approaches, namely coding and non-coding RNA analysis, whole transcriptome studies, and combinatorial applications, including SMA scores and biomarker panels. It is this visualization that underlines the multi-faceted approach for broad biomarker analysis in SMA, highlighting the diversity in sample sources and various molecular and non-molecular targets that could be analyzed for disease monitoring, assessment of progression, and evaluation of the treatment response

Fig. 2. RNAs in the neuromuscular system in spinal muscular atrophy (SMA) and their interactions. A complex interplay occurs between motor neurons (blue), glial cells (purple), and various RNA species. The cellular components of the neuromuscular system affected in SMA are shown on the left. The key RNA regulatory elements and their interactions in relation to protein expression are shown on the right. lncRNA, long non-coding RNA; circRNA, circular RNA; miRNA, microRNA; mRNA, messenger RNA. Pseudogenes are also depicted, as they can generate non-coding transcripts that function as ceRNAs, contributing to the RNA regulatory landscape relevant to SMA. The non-coding RNAs participate in competing endogenous RNA mechanisms, modulating gene expression by interacting with miRNAs. The abundance and regulatory roles of the RNA species in the central nervous system make them promising candidates for non-invasive biomarkers in SMA diagnosis and monitoring because they can be detected in body fluids (inspired by [150])