Apoptosis-Inducing Fibrillar Assemblies Imply a Common Mechanism for Inborn Error of Metabolism Disorders

Inborn error of metabolism (IEM) result in the accumulation of metabolites that could be toxic or interfere with normal function of the cell. Our group has previously demonstrated that phenylalanine can self-assemble to form amyloid-like fibrils possessing typical ultrastructural, biophysical and biological properties. To study whether these observations represent a general amyloid-like mechanism prevalent in other IEM disorders, we have screened metabolites that accumulate in IEM disorders. We reveal that several other metabolites can self-assemble to form ordered amyloid-like ultrastructure with the molecular dimensions and dye-binding specificity similar to canonical amyloid fibrils. In addition, we show that these assemblies trigger apoptotic programmed cell death, as observed for amyloid disorders. We demonstrate the discrete immunological entities of these metabolite amyloid-like assemblies, which can activate the immune system. Furthermore, we presented the ability of the metabolite assemblies to interact with model membranes, as known for their proteinaceous counterparts. Lastly, we present that two generic polyphenolic inhibitors of proteinaceous amyloid self-assembly can also restrict the formation of metabolite fibrils and reduce their cytotoxicity. These results suggest that the formation of amyloid-like self-assemblies by metabolites indicate to a general phenomenon of amyloid formation beyond proteins and peptides and offer a new innovative paradigm for IEM disorders. The immunologic entities demonstrated by the metabolite amyloids provides further indication to their role in the disease ethology. Finally, the less explored concept of IEM disorders as amyloid diseases may thus lead to the development of new therapeutic strategies in addition to the current dietary restrictions.