Glyoxal as a modulator for the GABA receptor response in C. elegans

Abstract

Human DJ-1, conserved in C. elegans, is known as one of early-onset genes of Parkinson’s disease despite of its obscure biochemical function. Methylglyoxal (MG), an intracellular metabolite from glucose, has been associated with neurodegenerative diseases including Parkinson’s disease. In recent, human DJ-1 is characterized as a novel glyoxalase which detoxifies glyoxal (GO) or methylglyoxal without any cofactors. We investigated effects of GO and MG in vivo, especially on behavior of Caenorhabditis elegans. In order to investigate how DJ-1 substrates, MG and glyoxal (GO), affect neuronal system, we use nematode ‘Caenorhabditis elegans’ (C. elegans) which is the only organism with completed connectome. C. elegans has an advantage in application to human for its conserved nerve system such as GABA signaling and glyoxalase system in human. MG and GO always produced, especially in neurons, are often referred as toxins. $\gamma$ -Aminobutyric acid (GABA) was known to act as a major neuromodulator of neuromuscular junction (NMJ) in C. elegans, regulating its coordinate movements. We found that GABA molecule itself, as well as MG and GO, change locomotion in dose-dependent manner. The GABAergic effects were observed by altering the physiological level of MG/GO, resulting in changes of behaviors, including the swimming cycle and speed. We found that GABA molecule itself, as well as MG and GO, change locomotion in dose-dependent manner. The GABAergic effects were observed by altering the physiological level of MG/GO, resulting in changes of behaviors, including the swimming cycle and speed. The effective range of glyoxals for speed change was different from that of toxicity. It implies that MG and GO may have distinct functions, not just toxins. The unc-49 and gbb-1/2 genes, encoding the $GABA_A$ and $GABA_B$ receptors of C. elegans, regulate body posture in locomotion in order to achieve coordinate behavior. The speed decrease by GO was not observed in both $\Delta$ gbb-1 and $\Delta$ gbb-2 strains, implying that gbb-1/2 are involved in the effect of GO. In addition, the $\Delta$ gbb-1 showed speed decrease when rescued by gbb-1 gene, which was observed in WT. MG also affects speed, although exact target of MG is obscure. We also observed combined and additive effects of GO and saclofen, a competitive $GABA_B$ receptor antagonist, likely suggesting that their effects merge in this receptor. Speed decrease is also observed in knock-out mutants of djr-1.1 and djr-1.2, which were reported as homologs of hDJ-1 in C. elegans. Therefore, we suggest the probability that non-motor symptoms of Parkinson’s disease can be attributed to GABAergic phenotypes caused by MG and GO accumulated by DJ-1 malfunction.