TY - JOUR
T1 - Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria
AU - Adler-Abramovich, Lihi
AU - Vaks, Lilach
AU - Carny, Ohad
AU - Trudler, Dorit
AU - Magno, Andrea
AU - Caflisch, Amedeo
AU - Frenkel, Dan
AU - Gazit, Ehud
N1 - Funding Information: 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.
PY - 2012/8
Y1 - 2012/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84864285157&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/nchembio.1002
DO - https://doi.org/10.1038/nchembio.1002
M3 - مقالة
SN - 1552-4450
VL - 8
SP - 701
EP - 706
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 8
ER -