HAGH, also known as hydroxyacylglutathione hydrolase, encodes glyoxalase 2, a mitochondrial and cytoplasmic protein of the metallo-β -lactamase family [2]. The glyoxalase system, in which HAGH-encoded glyoxalase 2 is the second enzyme, is responsible for detoxifying the α -ketothaldehyde methylglyoxal in cells, utilizing glutathione as a cofactor [2]. This system is involved in the oxidative stress pathway and plays a role in maintaining cellular homeostasis [1].

A study on schizophrenia patients found a nominally significant association with schizophrenia of rs11859266, a SNP in the intronic region of HAGH, although it did not survive multiple testing. In males, variants in HAGH, rs11859266 and rs3743852, showed significant associations with schizophrenia at allelic and genotype levels, with some persistence after multiple testing [3]. In Alzheimer's disease, plasma levels of HAGH protein were significantly elevated in APOE ε4 carrier AD patients, suggesting it may be a new blood-based biomarker related to the disease [1].

In conclusion, HAGH is crucial for the detoxification of methylglyoxal through the glyoxalase system and is associated with oxidative stress. Its genetic variants may be related to schizophrenia, especially in males, and HAGH protein levels are associated with Alzheimer's disease in APOE ε4 carriers. These findings from in vivo-like studies (involving human subjects) contribute to understanding the role of HAGH in these disease conditions [1,3].

References:

1. Ahmad, Shahzad, Milan, Marta Del Campo, Hansson, Oskar, Amin, Najaf, van Duijn, Cornelia M. 2020. CDH6 and HAGH protein levels in plasma associate with Alzheimer's disease in APOE ε4 carriers. In Scientific reports, 10, 8233. doi:10.1038/s41598-020-65038-5. https://pubmed.ncbi.nlm.nih.gov/32427856/

2. Scirè, Andrea, Cianfruglia, Laura, Minnelli, Cristina, Antognelli, Cinzia, Armeni, Tatiana. 2022. Glyoxalase 2: Towards a Broader View of the Second Player of the Glyoxalase System. In Antioxidants (Basel, Switzerland), 11, . doi:10.3390/antiox11112131. https://pubmed.ncbi.nlm.nih.gov/36358501/

3. Bangel, Fabian N, Yamada, Kazuo, Arai, Makoto, Stork, Oliver, Yoshikawa, Takeo. 2015. Genetic analysis of the glyoxalase system in schizophrenia. In Progress in neuro-psychopharmacology & biological psychiatry, 59, 105-110. doi:10.1016/j.pnpbp.2015.01.014. https://pubmed.ncbi.nlm.nih.gov/25645869/