Methylglyoxal Produced by Amyloid-beta Peptide-Induced Nitrotyrosination of Triosephosphate Isomerase Triggers Neuronal Death in Alzheimer's Disease
Por:
Tajes, M, Eraso-Pichot, A, Rubio-Moscardo, F, Guivernau, B, Ramos-Fernandez, E, Bosch-Morato, M, Guix, FX, Clarimon, J, Miscione, GP, Boada, M, Gil-Gomez, G, Suzuki, T, Molina, H, Villa-Freixa, J, Vicente, R, Munoz, FJ
Publicada:
1 ene 2014
Resumen:
Amyloid-beta peptide (A beta) 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 A beta(42) 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 A beta(42) 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 A beta 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 A beta oligomers. This occurs because of TPI nitrotyrosination, which affects both tyrosines associated with the catalytic center.
Filiaciones:
Tajes, M:
Univ Pompeu Fabra, Lab Mol Physiol & Channelopathies, Dept Ciencies Expt & Salut DCEXS, Barcelona 08003, Spain
Eraso-Pichot, A:
Univ Pompeu Fabra, Lab Mol Physiol & Channelopathies, Dept Ciencies Expt & Salut DCEXS, Barcelona 08003, Spain
Rubio-Moscardo, F:
Univ Pompeu Fabra, Lab Mol Physiol & Channelopathies, Dept Ciencies Expt & Salut DCEXS, Barcelona 08003, Spain
Guivernau, B:
Univ Pompeu Fabra, Lab Mol Physiol & Channelopathies, Dept Ciencies Expt & Salut DCEXS, Barcelona 08003, Spain
Ramos-Fernandez, E:
Univ Pompeu Fabra, Lab Mol Physiol & Channelopathies, Dept Ciencies Expt & Salut DCEXS, Barcelona 08003, Spain
Bosch-Morato, M:
Univ Pompeu Fabra, Lab Mol Physiol & Channelopathies, Dept Ciencies Expt & Salut DCEXS, Barcelona 08003, Spain
Guix, FX:
Univ Pompeu Fabra, Lab Mol Physiol & Channelopathies, Dept Ciencies Expt & Salut DCEXS, Barcelona 08003, Spain
Clarimon, J:
Hosp Santa Creu & Sant Pau, Dept Neurol, Alzheimer Lab, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Miscione, GP:
IMIM UPF, DCEXS, Res Program Biomed Informat, Computat Biochem & Biophys Lab, Barcelona, Spain
Univ Bologna, Dipartimento Chim G Ciamician, I-40126 Bologna, Italy
Boada, M:
Fundaci ACE Inst Catala Neurociencies Aplicades, Memory Clin, Barcelona, Spain
Univ Autonoma Barcelona VHIR UAB, Hosp Univ Vall dHebron Inst Recerca, Dept Neurol, Barcelona, Spain
Gil-Gomez, G:
IMIM Inst Hosp Mar Invest Med, Barcelona, Spain
Suzuki, T:
Hokkaido Univ, Grad Sch Pharmaceut Sci, Neurosci Lab, Sapporo, Hokkaido, Japan
Molina, H:
UPF, DCEXS, Prote Unit, Barcelona, Spain
CRG, Barcelona, Spain
Villa-Freixa, J:
IMIM UPF, DCEXS, Res Program Biomed Informat, Computat Biochem & Biophys Lab, Barcelona, Spain
Univ Vic, Escola Politecn Super, Girona, Spain
Vicente, R:
Univ Pompeu Fabra, Lab Mol Physiol & Channelopathies, Dept Ciencies Expt & Salut DCEXS, Barcelona 08003, Spain
Munoz, FJ:
Univ Pompeu Fabra, Lab Mol Physiol & Channelopathies, Dept Ciencies Expt & Salut DCEXS, Barcelona 08003, Spain
Green Accepted, Green Published
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