All Roads Lead to Rome: Non-canonical Modulators of RNA Metabolism in ALS Pathogenesis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. Aberrant RNA metabolism is one of its most consistent molecular features, and ALS has long been framed as a disease of RNA-binding proteins (RBPs), given that mutations in RBPs are among the most frequent genetic causes of ALS. However, a growing number of ALS-associated genes encode proteins that lack canonical RNA-binding domains; nonetheless, their mutations also disrupt RNA homeostasis. This review examines how these non-canonical disease modulators perturb RNA metabolism. We group these factors into three functional classes. One includes proteostasis regulators, whose dysfunction impairs protein quality control and promotes the accumulation of aggregation-prone RBPs in cytoplasmic inclusions and persistent stress granules. Another involves factors that elicit RNA toxicity or disrupt ribonucleoprotein organization, including GGGGCC repeat expansion in C9ORF72 and CAG repeat expansion in ATXN1. The third class comprises factors governing axonal RNA granule transport. Across these categories, a shared consequence is the disruption of mRNA processing, stability, localization, and translation in motor neurons. We further discuss how epitranscriptomic dysregulation, particularly altered m6A and m1A modification states, may contribute to ALS pathology. We also discuss the therapeutic implications of this mechanistic convergence in defective RNA metabolism in ALS.