If not degraded or modified, reactive metabolites damage cells. One group of reactive metabolites is the α-dicarbonyls (α-DCs), which damage proteins, lipids, and DNA through a nonenzymatic form of glycosylation (glycation). Methylglyoxal (MGO) is an α-DC that accumulates with age and damages nerves and arteries. MGO also accumulates in patients with neurodegenerative disorders and in diabetic patients. In diabetic patients, the accumulation results from increased glycolytic flux, which produces excess MGO. Chaudhuri et al. found that Caenorhabditis elegans lacking the glyoxalase GLOD-4, an enzyme that metabolizes and detoxifies MGO, exhibited MGO accumulation, reduced motility, and neuronal damage. Similar to diabetic patients, who initially experience hypersensitivity and then later loss of sensation, worms deficient in glod-4 were initially hypersensitive to touch but eventually lost sensitivity to touch. Treating wild-type C. elegans with MGO or rearing them on a high-glucose diet phenocopied loss of glod-4. Genetic experiments revealed that accumulation of α-DCs activated the nociceptive transient receptor potential ion channel TRPA-1, which stimulated signaling through the calcium/calmodulin-dependent kinase II (CaMKII) homolog UNC-43 and the p38 mitogen-activated protein kinases PMK-1 and SEK-1 to stimulate activity of the transcription factor SKN-1. SKN-1 is homologous to vertebrate Nrf2, which stimulates the expression genes involved in antioxidant and xenobiotic responses. MGO-induced activation of SKN-1 stimulated the transcription of glod-4 as well as djr-1.1 and djr-1.2, which encode homologs of the human glyoxalase DJ1. Screening a library of natural products for compounds that rescued the phenotypes of glod-4 mutants identified podocarpic acid, a component of the resin of some conifers. Treating glod-4 mutants with podocarpic acid or the NRF2 activator α-lipoic acid stimulated activation of SKN-1 and reduced the accumulation of MGO in a manner that depended on TRPA-1. Experiments in human and rat cultured cells indicated that this α-DC detoxification pathway is conserved in vertebrates and that podocarpic acid can reduce the neurotoxic effects of MGO. This study not only delineates the pathway through which α-DCs induce the machinery necessary for their detoxification, it also demonstrates the usefulness of C. elegans for identifying compounds that could be developed into therapeutics for human patients.
J. Chaudhuri, N. Bose, J. Gong, D. Hall, A. Rifkind, D. Bhaumik,
T. H. Peiris, M. Chamoli, C. H. Le, J. Liu, G. J. Lithgow, A. Ramanathan, X. Z. S. Xu, P. Kapahi, A Caenorhabditis elegans model elucidates a conserved role for TRPA1-Nrf signaling in reactive α-dicarbonyl detoxification. Curr. Biol. 26, 3014–3025 (2016). [PubMed]