Amyloid-Inducing Agents via Metabolite Self-Assembly Expands the Boundary of Prion Concept beyond Proteins

The prion concept fundamentally signifies the intrinsic cross-seeding potential of misfolded protein-generated amyloid entities to efficiently induce amyloid aggregation in normally folded proteins leading to formation of cytotoxic amyloid structures. A conformational crosstalk between the prion particle and the interacting protein appears critical for the molecular origin of seeded-aggregation. However, the intricacies of protein specificity, as a prerequisite for the onset of cross-seeding, hold negligible relevance to the pathobiology of amyloid-linked diseases because the amyloid-deposits are heteroprotein assemblies, and there is adequate evidence that substantiates the occurrence of sequence-independent amyloid-cross-seeding/co-aggregation reactions between diverse protein types. Importantly, extensive research on the self-assembly of single metabolites into cytotoxic amyloid-like entities containing cross-seeding competent conformers has certainly widened the boundary of prion concept much beyond the territory of proteins and peptides. Three important observations: 1) sequence-independent cross-seeding and co-aggregation among proteins; 2) efficient amyloid-cross-seeding of proteins triggered by self-assembled metabolite-nanostructures, and 3) molecular self-assembly of metabolites induced by pre-formed protein amyloid-seeds, propose a synergetic interplay between the amyloidogenic proteins and self-assembly-prone metabolites that can act as a key regulator for the overall amyloidogenesis mechanism. This review on the self-assembly of biologically relevant metabolites into amyloid-mimicking nanostructures mainly highlights their cytotoxic properties and cross-seeding potential, particularly focusing on the significance of the metabolite-aggregation in the etiology of amyloid hypothesis.