Unraveling the mechanism of β-N-oxalyl-α,β-diaminopropionic acid (β-ODAP) induced excitotoxicity and oxidative stress, relevance for neurolathyrism prevention.
β-N-Oxalyl-α,β-diaminopropionic acid (β-ODAP) is a plant metabolite present in Lathyrus sativus (L. Sativus) seeds that is proposed to be responsible for the neurodegenerative disease neurolathyrism. This excitatory amino acid binds to α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and several lines of evidence indicate that β-ODAP triggers motor neuron degeneration by inducing excitotoxic cell death and increasing oxidative stress. In addition, this toxin is known to disturb the mitochondrial respiration chain and recent data indicate that β-ODAP may inhibit the uptake of cystine thereby compromising the cells' abilities to cope with oxidative stress. Recent work from our group furthermore suggests that β-ODAP disturbs the cellular Ca(2+) homeostasis machinery with increased Ca(2+) loading in the endoplasmic reticulum (ER)-mitochondrial axis. In this review, we aim to integrate the various mechanistic levels of β-ODAP toxicity into a consistent pathophysiological picture. Interestingly, the proposed cascade contains several aspects that are common with other neurodegenerative diseases, for example amyotrophic lateral sclerosis (ALS). Based on these mechanistic insights, we conclude that dietary supplementation with methionine (Met) and cysteine (Cys) may significantly lower the risk for neurolathyrism and can thus be considered, in line with epidemiological data, as a preventive measure for neurolathyrism.
Department of Basic Medical Sciences - Physiology Group, Faculty of Medicine and Health Sciences, De Pintelaan 185, Block B, 3th Floor, Ghent University, B-9000 Ghent, Belgium.
M
M
Van Moorhem
F
F
Lambein
L
L
Leybaert
D000599:Amino Acids, Diamino / Q000737:chemistry* / Q000506:poisoning*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D003553:Cystine / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D018846:Excitatory Amino Acids / Q000378:metabolism; D007842:Lathyrism / Q000139:chemically induced* / Q000517:prevention & control*; D027807:Lathyrus / Q000737:chemistry; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress
D000599:Amino Acids, Diamino; D018846:Excitatory Amino Acids; C100126:oxalyldiaminopropionic acid; D003553:Cystine; D002118:Calcium