title: Methylglyoxal produced by amyloid-β peptide-induced nitrotyrosination of triosephosphate isomerase triggers neuronal death in Alzheimer's disease.
abstract: Amyloid-β peptide (Aβ) aggregates induce nitro-oxidative stress, contributing to the characteristic neurodegeneration found in Alzheimer's disease (AD). One of the most strongly nitrotyrosinated proteins in AD is the triosephosphate isomerase (TPI) enzyme which regulates glycolytic flow, and its efficiency decreased when it is nitrotyrosinated. The main aims of this study were to analyze the impact of TPI nitrotyrosination on cell viability and to identify the mechanism behind this effect. In human neuroblastoma cells (SH-SY5Y), we evaluated the effects of Aβ42 oligomers on TPI nitrotyrosination. We found an increased production of methylglyoxal (MG), a toxic byproduct of the inefficient nitro-TPI function. The proapoptotic effects of Aβ42 oligomers, such as decreasing the protective Bcl2 and increasing the proapoptotic caspase-3 and Bax, were prevented with a MG chelator. Moreover, we used a double mutant TPI (Y165F and Y209F) to mimic nitrosative modifications due to Aβ action. Neuroblastoma cells transfected with the double mutant TPI consistently triggered MG production and a decrease in cell viability due to apoptotic mechanisms. Our data show for the first time that MG is playing a key role in the neuronal death induced by Aβ oligomers. This occurs because of TPI nitrotyrosination, which affects both tyrosines associated with the catalytic center.
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Tajes
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Abel
authors.initials: A
authors.lastname: Eraso-Pichot
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Fanny
authors.initials: F
authors.lastname: Rubio-Moscardó
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Biuse
authors.initials: B
authors.lastname: Guivernau
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Ramos-Fernández
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Mònica
authors.initials: M
authors.lastname: Bosch-Morató
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Francesc Xavier
authors.initials: FX
authors.lastname: Guix
authors.affiliation: Alzheimer Laboratory, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimón
authors.affiliation: Computational Biochemistry and Biophysics Laboratory, Research Program on Biomedical Informatics, DCEXS, IMIM/UPF, Barcelona, Spain Dipartimento di Chimica "G. Ciamician", Universitá degli Studi di Bologna, Italy.
authors.forename: Gian Pietro
authors.initials: GP
authors.lastname: Miscione
authors.affiliation: Memory Clinic, Fundació ACE. Institut Català de Neurociències Aplicades, Barcelona, Spain Neurology Department, Hospital Universitari Vall d'Hebron-Institut de Recerca, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain.
authors.forename: Mercé
authors.initials: M
authors.lastname: Boada
authors.affiliation: IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Gil-Gómez
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Proteomics Unit, DCEXS, UPF and Centre de Regulació Genómica (CRG), Barcelona, Spain.
authors.forename: Henrik
authors.initials: H
authors.lastname: Molina
authors.affiliation: Computational Biochemistry and Biophysics Laboratory, Research Program on Biomedical Informatics, DCEXS, IMIM/UPF, Barcelona, Spain Escola Politécnica Superior, Universitat de Vic, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Villà-Freixa
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Vicente
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Muñoz
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001921:Brain / Q000503:physiopathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D003198:Computer Simulation; D005260:Female; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D008958:Models, Molecular; D009474:Neurons / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics; D011765:Pyruvaldehyde / Q000378:metabolism*; D014305:Triose-Phosphate Isomerase / Q000235:genetics / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D011765:Pyruvaldehyde; D014305:Triose-Phosphate Isomerase
keywords: 3-nitrotyrosine; Alzheimer's disease; amyloid; apoptosis; methylglyoxal; triose-phosphate isomerase