Ribonucleic acid as an active driver of protein aggregation in neurodegeneration

Neurodegeneration has traditionally been largely attributed to protein aggregation, yet ribonucleic acid (RNA) has emerged as an active driver of pathology. Expanded repeat RNAs, misregulated RNA-binding proteins, and aberrant RNA–protein interactions can directly or indirectly trigger neuronal dysfunction, although the distinction between the two mechanisms might, in some cases, be loose. RNA modulates prion-like aggregation, scaffolds liquid–liquid phase separation, and either promotes or inhibits protein assembly, depending on RNA sequence and structure. The aim of this review is to discuss our current understanding of RNA's dual role—as a facilitator of aggregation or as a potential therapeutic target—revealing new mechanistic insights into diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and spinocerebellar ataxias. We highlight RNA metabolism as a central determinant of neuronal vulnerability.