Non-coding RNAs in neurodegeneration: an axis-based, evidence-tiered mechanistic synthesis

Evidence supporting the involvement of non-coding RNAs (ncRNAs) in neuronal plasticity and susceptibility has been fragmented across different diseases and ncRNA subtypes. We propose an evidence-tiered, axis-based framework integrating microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) across major neurodegenerative disorders. We have focused on studies that have attempted to establish links between ncRNAs and disease pathogenesis through functional perturbation, validation, and/or rescue in relevant disease models. To facilitate cross-disease comparison, we have categorized these studies along four axes of proteostasis/protein aggregation, neuroinflammation, synaptic/circuit dysfunction, and mitochondrial/autophagy dysfunction. Overall, these ncRNAs have been reported to function as modulators and potential indicators of bioenergetic stress, influencing glial cell function, neuronal survival, metabolic vulnerability, and network plasticity. We have highlighted common regulatory modules, including the role of miRNAs in modulating autophagy and inflammatory-metabolic coupling, lncRNAs in regulating amyloid/synuclein-related processes, and circRNA-mediated miRNA/RBP modules in regulating processes involving mitochondria, while also pointing out discrepancies. We have also discussed the possibility of ncRNA panels and therapeutics, facilitated by advances in delivery strategies, for the discovery of biomarkers and drug targets, while also pointing out some of the challenges that need to be addressed, including heterogeneity of evidence, cell-type specificity, blood-brain barrier constraints, and off-target effects.