Methylglyoxal produced by amyloid-beta peptide-induced nitrotyrosination of triosephosphate isomerase triggers neuronal death in alzheimer's disease

Marta Tajes, Abel Eraso-Pichot, Fanny Rubio-Moscardo, Biuse Guivernau, Eva Ramos-Fernandez, Monica Bosch-Morato, Francesc Xavier Guix, Jordi Clarimon, Gian Pietro Miscione, Merce Boada, Gabriel Gil-Gomez, Toshiharu Suzuki, Henrik Molina, Jordi Villa-Freixa, Ruben Vicente, Francisco J. Munoz

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Resum

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.
Idioma originalAnglès
Pàgines (de-a)273-288
Nombre de pàgines16
RevistaJournal of Alzheimer's Disease
Volum41
Número1
DOIs
Estat de la publicacióPublicada - 2014
Publicat externament

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