Metabolite amyloids: a new paradigm for inborn error of metabolism disorders

Abstract

The formation of ordered amyloid assemblies is associated with major human degenerative disorders, including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. Amyloid fibrils are elongated nanoscale structures that bind to specific dyes (including thioflavin T and Congo red). Amyloid fibrillar assemblies or their early intermediates are known to induce apoptotic cytotoxic effect. Until recently, amyloid fiber formation was observed only with proteins and peptides. We reported in 2012 that a single amino acid, phenylalanine, could also form typical amyloid fibrils with the same morphology, dye-binding specificity, and electron diffraction pattern as protein amyloids. X-ray crystallography demonstrated the formation of supramolecular β-sheet-like organization by phenylalanine at its zwitterionic form. Metabolite amyloids had pronounced cytotoxicity that could be depleted by treatment with antibodies raised against the phenylalanine structures. We suggested that the observed amyloid formation could explain some of the symptoms observed in phenylketonuria (PKU) upon the accumulation of phenylalanine. Follow-up studies by other groups revealed the ability of phenylalanine amyloids to bind to membranes, as observed with protein amyloids. Furthermore, the doxycycline amyloid formation inhibitor was shown to also affect the formation of phenylalanine amyloids. In 2015, it was reported that other metabolites involved in metabolic disorders, including adenine, uracil, tyrosine, and orotic acid, could form amyloid-like assemblies. It was further demonstrated that the assemblies induce apoptotic cell death. Taken together, we suggest a new hypothesis to understand the etiology of degenerative processes observed in inborn error of metabolism disorders and indicate new avenues for treatment.

Quinolinic Acid Amyloid-like Fibrillar Assemblies Seed α-Synuclein Aggregation

“…Millions of people worlwide are afflicted with neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis, which are characterized by progressive dysfunction of the central nervous system [1][2][3][4]. The pathology of these ailments is associated with several amyloidogenic proteins and polypeptides, including β-amyloid in AD [5,6], α-synuclein in PD [7] and TDP-43 in amyotrophic lateral sclerosis [8],which form structures exhibiting amyloid-like characteristics [12][13][14][15][16]. Each of these metabolites individually accumulates in specific inborn error of metabolism disorders, which all manifest severe neurological abnormalities [17,18].…”

Phenylketonuria, co‐morbidity, and ageing: A review

“…In common with AD and Parkinson's disease (PD) are the formation of amyloid fibrils that are toxic to neuronal cells (ie, β-amyloid in AD, α-synuclein in PD, and [elevated] Phe in PKU). [37][38][39] One study of 40 people has looked at Phe levels in AD, showing higher Phe levels in a subgroup of patients. 40 A single study looked at the pathological hallmarks of AD, tau and amyloid, in the cerebrospinal fluid of 15 AwPKU (mean age 38.2 years), though, given the research targets and young age of participants, results are inconclusive.…”

Functional metabolite assemblies—a review

“…These simple building blocks, such as phenylalanine, uric acid, uracil, orotic acid, tyrosine, cysteine, and adenine, can organize by non-covalent interactions, including hydrogen bonding, aromatic interactions, and van der Waals interactions, to form ordered supramolecular assemblies. Remarkably, some of the assembled metabolite structures present amyloid-like biophysical, biochemical, and cytotoxic properties (Adler-Abramovich et al 2012; Shaham-Niv et al 2015; Gazit 2016). Canonical amyloids are insoluble fibrillar protein deposits with an underlying cross-β structure initially discovered in the context of human degenerative diseases (Rochet and Lansbury Jr 2000; Makin and Serpell 2005; Chiti and Dobson 2006).…”