Phenylketonuria (PKU), a metabolic disease marked by the accumulation of the amino acid phenylalanine, has hallmark features of amyloid disease including a buildup of toxic fibrils, reports a study published online this week in Nature Chemical Biology.
In PKU, accumulation of phenylalanine has been thought to be neurotoxic, but the mechanism of toxicity had not been determined. Because of this toxicity, patients with the disease must carefully control phenylalanine intake. In Alzheimer’s disease (AD) and other amyloid diseases marked by formation of protein fibril aggregates, aromatic amino acids such as phenylalanine are known to be important for acceleration of the amyloid assembly process. Specifically, two adjacent phenylalanine residues in the amyloid beta protein seem to mediate the intermolecular interaction between polypeptide chains required for fibril aggregate assembly seen in AD.
Ehud Gazit and colleagues now make a direct connection between the two diseases by demonstrating that phenylalanine alone can form toxic fibrils. Phenylalanine, at concentrations that exist in PKU, self-assembles into amyloid-like fibrils. A mouse model of PKU expressed antibodies against phenylalanine fibrils, presumably as a consequence of the disease, as they were not found in non-diseased mice. The brains of the diseased mice contained plaques, the hallmark of amyloid diseases. These results provide a greater molecular understanding of PKU and suggest that treatments aimed at the classical amyloid diseases might prove useful for PKU as well.