Oxidation of methionine 35 reduces toxicity of the amyloid beta-peptide(1-42) in neuroblastoma cells (IMR-32) via enzyme methionine sulfoxide reductase A expression and function.
The beta amyloid peptide (Abeta), the major protein component of brain senile plaques in Alzheimer's disease, is known to be directly responsible for the production of free radicals that may lead to neurodegeneration. Our recent evidence suggest that the redox state of methionine residue in position 35 (Met-35) of Abeta has the ability to deeply modify peptide's neurotoxic actions. Reversible oxidation of methionine in proteins involving the enzyme methionine sulfoxide reductase type A (MsrA) is postulated to serve a general antioxidant role and a decrease in MsrA has been implicated in Alzheimer's disease. In rat neuroblastoma cells (IMR-32), we used Abeta(1-42), in which the Met-35 is present in the reduced state, with a modified peptide with oxidized Met-35 (Abeta(1-42)Met35(OX)), as well as an Abeta-derivative in which Met-35 is substituted with norleucine (Abeta(1-42)Nle35) to investigate the relationship between Met-35 redox state, expression and function of MsrA and reactive oxygen species (ROS) generation. The obtained results shown that MsrA activity, as well as mRNA levels, increase in IMR-32 cells treated with Abeta(1-42)Met35(OX), differently to that shown by the reduced derivative. The increase in MsrA function and expression was associated with a decline of ROS levels. None of these effects were observed when cells were exposed to Abeta containing oxidized Met35 (Abeta1-42)Met35(OX). Taken together, the results of the present study indicate that the differential toxicity of Abeta peptides containing reduced or oxidised Met-35 depends on the ability of the latter form to reduce ROS generation by enhancing MsrA gene expression and function and suggests the therapeutic potential of MsrA in Alzheimer's disease.
Misiti
Francesco
F
Department of Health and Motor Sciences, University of Cassino, V.S. Angelo, Polo didattico della Folcara, 03043 Cassino (FR), Italy. f.misiti@unicas.it
Clementi
M Elisabetta
ME
Giardina
Bruno
B
D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D018076:DNA, Complementary / Q000096:biosynthesis / Q000302:isolation & purification; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D051150:Methionine Sulfoxide Reductases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009447:Neuroblastoma; D009646:Norleucine / Q000737:chemistry; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry / Q000633:toxicity*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013113:Spin Labels
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D003497:Cyclic N-Oxides; D018076:DNA, Complementary; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D013113:Spin Labels; C075222:amyloid beta-protein (1-42); D012313:RNA; D009646:Norleucine; D008715:Methionine; D051150:Methionine Sulfoxide Reductases; C001803:tempol; C013111:methionine sulfoxide