Several IDPs show strong relationships to diseases, with many of these disease-related IDPs often forming protein aggregates including toxic oligomers, insoluble fibrils and amyloids. In the case of protein misfolding diseases, the folded protein will eventually form protein aggregates. Both processes are thus very similar. In the case of disease-related IDPs, the ‘local structural element’ is the key molecular species that forms the ‘nucleus’ of protein aggregation while in the case of protein misfolding diseases it is replaced by a ‘partly unfolded molecule’.It is believed that compactly folded proteins are soluble and thermodynamically stable under physiological conditions at body temperature, therefore both transient states are called ‘aggregation-prone’ species.For many folded proteins associated with misfolding diseases, only a few critical amino acid substitutions may drastically affect their pathogenicity, caused by increasing population of partially unfolded species by the mutation. When two or more aggregation-prone monomer species encounter each other, a small invisible oligomer ‘nucleus’ forms which drastically enhances the self-assembly rate of the protein monomer into aggregates or fibrils. This phenomenon is known as a ‘nucleation-dependent process’.In most cases, an elevated concentration of aggregation-prone species is important for nucleation, which is achieved by the neutralization of electrostatic repulsion at the isoelectric point or contact of monomer species with gas-liquid or liquid-membrane interfaces. Absorption of monomer species on membrane surfaces is one of the major factors that initiates nucleation.Regardless of whether the polymerization process is nucleation-dependent or independent, most aggregation formation processes are irreversible. One possible explanation of why such protein aggregation is irreversible is ‘supersaturation.’ Recently, many protein aggregates and amyloid formations were shown to be strongly related to the supersaturating state of the monomer species.From extensive analyses of IDPs and aggregation-prone sequences, it was observed that solubility-enhancing residues or sequences often associated with aggregation-prone regions.Based on this observation, they proposed a ‘gatekeeping residue’ hypothesis, in which mutation(s) on the solubility-enhancing residues may become a trigger for aggregation. The hypothesis may connect a gene mutation, the physicochemical property of disease-related IDPs, and pathogenesis of protein aggregation.