Phenylketonuria (PKU) is characterized by phenylalanine accumulation and progressive mental retardation caused by an unknown mechanism. We demonstrate that at pathological concentrations, phenylalanine self-assembles into fibrils with amyloid-like morphology and well-ordered electron diffraction. These assemblies are specifically recognized by antibodies, show cytotoxicity that can be neutralized by the antibodies and are present in the hippocampus of model mice and in parietal cortex brain tissue from individuals with PKU. This is, to our knowledge, the first demonstration that a single amino acid can form amyloid-like deposits, suggesting a new amyloidosis-like etiology for PKU.
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We thank R. Shaltiel-Karyo for confocal microscopy analysis, S. Wolf for the electron diffraction analysis, L. Buzhansky for help with the NMR and HPLC analysis, J. Delarea for help with TEM and SEM experiments, Z. Barkay for help with the SEM and ESEM analysis, S.-C. Jung (Ewha Womans University, Korea) for BTBR-Pahenu2 mouse plasma and tissue samples, C. Troakes (London Neurodegenerative Diseases Brain Bank, King's College London and part of BrainNet Europe) and T. Arzberger (Centre for Neuropathology and Prion Research, München) for brain tissue samples, I. Benhar and members of the Gazit laboratory for helpful discussions. L.A.-A. gratefully acknowledges the support of the Colton Foundation. This work was partly supported by the Israel Science Foundation–Legacy Heritage Biomedical Science Partnership grant 862/09 and the Alzheimer's Association grant NIRG-11-205535 (to D.F.). The work in the A.C. group was supported by the Swiss National Science Foundation.
The authors declare no competing financial interests.
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Adler-Abramovich, L., Vaks, L., Carny, O. et al. Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria. Nat Chem Biol 8, 701–706 (2012). https://doi.org/10.1038/nchembio.1002
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