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.
Highlights
The maintenance of metabolite homeostasis is an important part of cellular physiology, yet the accumulation of metabolites was observed in various diseases when phenotypic variations occur
Additional study demonstrated the cross-seeding of proteins by homogentisic acid (HGA), a metabolite related to alkaptonuria [24], a rare Inborn error of metabolism (IEM) disorder which was lately classified as secondary amyloidosis
Phenylalanine, tryptophan and tyrosine metabolism is commonly altered in Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), 5 PKU and Huntington’s disease, and metabolism of the first two is altered in Alzheimer’s disease (AD) [67,68,69,70]
Summary
Many diseases stem directly from variation in activity, folding and stability of proteins. In PKU, the blood concentration of phenylalanine can reach values over 1.2 mM [8,9] in untreated patients as compared with 35–85 mM in healthy individuals Another characteristic of metabolites, which until recently was attributed solely to proteins and peptides, is their ability to form ordered amyloid-like assemblies [10,11,12,13]. It can be hypothesized that part of the pathologies reported in IEM disorders are a result of metabolite accumulation and amyloid formation This hypothesis was further supported by demonstrating the presence of phenylalanine deposits in post-mortem brain sections of PKU patients using immunohistochemistry and Congo red staining [13]
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