Significance Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with wide clinical variability and a complex pathogenesis. One of the hallmarks of ALS is the presence of diverse inclusions formed by apparently disparate misfolded proteins, which are unrelated in sequence, structure, function, and localization. Many of these proteins, in addition, are not the usual interaction partners of the primary inclusion-forming ALS-related proteins (SOD1, TDP-43, and FUS). Here, we show that a common feature of these coaggregating proteins is their metastability to aggregation in spinal motor neurons. These results suggest that as protein homeostasis becomes progressively impaired in ALS, supersaturated proteins in an ALS-specific group fail to be maintained in their soluble states, leading to their presence in ALS-associated inclusions.