Age-dependent changes of glyoxalase I expression in human brain

Institut für Pathologie, University of Leipzig, Leipzig, Saxony, Germany
Neurobiology of Aging (Impact Factor: 5.01). 07/2006; 27(6):815-22. DOI: 10.1016/j.neurobiolaging.2005.04.006
Source: PubMed


Increased modification and crosslinking of proteins by advanced glycation end products (AGEs) is a characteristic feature of aging, and contributes to the formation of many of the lesions of neurodegenerative diseases including neurofibrillary tangles and amyloid plaques in Alzheimer's disease. Therefore, defense mechanisms against AGE formation or detoxification of their precursors such as the glyoxalase system are of particular interest in aging research. Thus, we investigated the age-dependent protein expression, the activity as well as the RNA level of glyoxalase I in Brodmann area 22 (auditory association area of superior temporal gyrus) of the human cerebral cortex. Our immunohistochemical results demonstrate the localization of glyoxalase I in neurons, predominantly pyramidal cells, as well as in astroglia, located predominantly in the subpial region. The number of glyoxalase I expressing neurons and astroglia increases with age, with a peak at approximately 55 years, and progressively decreases thereafter. These results were confirmed by biochemical investigations in total brain tissue, where the RNA, the protein level as well as the activity of glyoxalase I enzyme were analyzed in different age groups. In conclusion, the increase in glyoxalase I expression up to the age of 55 may be a compensatory mechanism against high oxoaldyde levels and the accumulation of AGEs. However, the decline of glyoxalase expression and activity in old age, possibly caused by impairment in transcription or/and translation, may subsequently lead to increased levels of reactive carbonyl compounds, followed by protein crosslinking, inflammation, oxidative stress and neuronal degeneration.

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    • "The lack of control for these confounding variables may well explain the discrepancy between our results and those previously reporting the association of ASD with the A332 (Glu111), and not the C332 (A111) allele (Barua et al., 2011; Junaid et al., 2004). In addition to small sample sizes and to the inclusion of patients with Batten disease or fragile-X syndrome as controls (Junaid et al., 2004), a lack of control for affection status and age on enzymatic activity measures obtained from AGRE cell lines selected by genotype (Barua et al., 2011) raises caution on these results in light of the present and of previous studies (Kuhla et al., 2006; Mailankot et al., 2009; Sharma-Luthra and Kale, 1994). On the other hand, the consistency between our genetic and biochemical findings, and between rs4942 effects in blood and brain, speaks against our data set being spurious, increasing confidence in the pathophysiological relevance of the present results. "
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    ABSTRACT: Glyoxalase I (GLO1) is a homodimeric Zn(2+)-dependent isomerase involved in the detoxification of methylglyoxal and in limiting the formation of advanced glycation end-products (AGE). We previously found the rs4746 A332 (Glu111) allele of the GLO1 gene, which encodes for glyoxalase I, associated with "unaffected sibling" status in families with one or more children affected by Autism Spectrum Disorder (ASD). To identify and characterize this protective allele, we sequenced GLO1 exons and exon-intron junctions, detecting two additional SNPs (rs1049346, rs1130534) in linkage disequilibrium with rs4746. A family-based association study involving 385 simplex and 20 multiplex Italian families yielded a significant association with autism driven only by the rs4746 C332 (Ala111) allele itself (P < 0.05 and P < 0.001 under additive and dominant/recessive models, respectively). Glyoxalase enzymatic activity was significantly reduced both in leukocytes and in post-mortem temporocortical tissue (N = 38 and 13, respectively) of typically developing C332 allele carriers (P < 0.05 and <0.01), with no difference in Glo1 protein levels. Conversely, AGE amounts were significantly higher in the same C332 post-mortem brains (P = 0.001), with a strong negative correlation between glyoxalase activity and AGE levels (τ = -0.588, P < 0.01). Instead, 19 autistic brains show a dysregulation of the glyoxalase-AGE axis (τ = -0.209, P = 0.260), with significant blunting of glyoxalase activity and AGE amounts compared to controls (P < 0.05), and loss of rs4746 genotype effects. In summary, the GLO1 C332 (Ala111) allele confers autism vulnerability by reducing brain glyoxalase activity and enhancing AGE formation, but years after an autism diagnosis the glyoxalase-AGE axis appears profoundly disrupted, with loss of C332 allelic effects.
    Journal of Psychiatric Research 08/2014; 59. DOI:10.1016/j.jpsychires.2014.07.021 · 3.96 Impact Factor
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    • "However, glutathione levels are usually depleted in chronic diabetes or AD cases. Similarly, other cellular antioxidant mechanisms, e.g., those involving superoxide dismutase and glyoxalase are also downregulated in cases of AD [62] [63]. Alternatively, increased concentrations of HNE are countered by the cellular expressions of antioxidant heat shock proteins, heme oxygenase-1 (HO- 1), and thioredoxin reductase-1 (Trx-R1) in cases of diabetic nephropathy [61] and AD [56,64,65]. "
    Dataset: C513

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