Seeding of proteins into amyloid structures by metabolite assemblies may clarify certain unexplained epidemiological associations

Abstract

The accumulation of various metabolites appears to be associated with diverse human diseases. However, the aetiological link between metabolic alteration and the observed diseases is still elusive. This includes the correlation between the abnormally high levels of homocysteine and quinolinic acid in Alzheimer's disease, as well as the accumulation of oncometabolites in malignant processes. Here, we suggest and discuss a possible mechanistic insight into metabolite accumulation in conditions such as neurodegenerative diseases and cancer. Our hypothesis is based on the demonstrated ability of metabolites to form amyloid-like structures in inborn error of metabolism disorders and the potential of such metabolite amyloids to promote protein aggregation. This notion can provide a new paradigm for neurodegeneration and cancer, as both conditions were linked to loss of function due to protein aggregation. Similar to the well-established observation of amyloid formation in many degenerative disorders, the formation of amyloids by tumour-suppressor proteins, including p53, was demonstrated in malignant states. Moreover, this new paradigm could fill the gap in understanding the high occurrence of specific types of cancer among genetic error of metabolism patients. This hypothesis offers a fresh view on the aetiology of some of the most abundant human maladies and may redirect the efforts towards new therapeutic developments.

Keywords: amyloid seeding; inborn error of metabolism; mechanism of neurodegeneration; metabolite accumulation; metabolite amyloids; oncometabolites.

Figure 1.

Scheme of the biosynthetic pathway downstream to phenylalanine. When enzyme deficiencies occur, specific metabolites accumulate (denoted in red), leading to particular disorders (denoted in brown). PAH, phenylalanine hydroxylase; TAT, tyrosine aminotransferase; HPPD, ρ-hydroxyphenylpyruvate dioxygenase; HGD, homogentisate 1,2-dioxygenase; MAAI, maleylacetoacetate isomerase; FAH, fumarylacetoacetase; FH, fumarate hydratase.

Figure 2.

Metabolite seeding hypothesis. A schematic putative model for the seeding of proteins by metabolite assemblies. Accumulated metabolites self-assemble into ordered structures. In turn, the structures serve as seeds to increase further aggregation of proteins. Loss of function of different proteins induces various pathological effects, as shown on the right.