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- Title
Role of the Glyoxalase System in Astrocyte-Mediated Neuroprotection.
- Authors
Bélanger, Mireille; Jiangyan Yang; Petit, Jean-Marie; Laroche, Thierry; Magistretti, Pierre J.; Allaman, Igor
- Abstract
The glyoxalase system is the most important pathway for the detoxification of methylglyoxal (MG), a highly reactive dicarbonyl compound mainly formed as a by-product of glycolysis. MG is a major precursor of advanced glycation end products (AGEs), which are associated with several neurodegenerative disorders. Although the neurotoxic effects of MG and AGEs are well characterized, little is known about the glyoxalase system in the brain, in particular with regards to its activity in different neural cell types. Results of the present study reveal that both enzymes composing the glyoxalase system [glyoxalase-1 (Glo-1) and Glo-2] were highly expressed in primary mouse astrocytes compared with neurons, which translated into higher enzymatic activity rates in astrocytes (9.9- and 2.5-fold, respectively). The presence of a highly efficient glyoxalase system in astrocytes was associated with lower accumulation of AGEs compared with neurons (as assessed by Western blotting), a sixfold greater resistance to MG toxicity, and the capacity to protect neurons against MG in a coculture system. In addition, Glo-1 downregulation using RNA interference strategies resulted in a loss of viability in neurons, but not in astrocytes. Finally, stimulation of neuronal glycolysis via lentiviral-mediated overexpression of 6-phosphofructose- 2-kinase/fructose-2,6-bisphosphatase-3 resulted in increased MG levels and MG-modified proteins. Since MG is largely produced through glycolysis, this suggests that the poor capacity of neurons to upregulate their glycolytic flux as compared with astrocytes may be related to weaker defense mechanisms against MG toxicity. Accordingly, the neuroenergetic specialization taking place between these two cell types may serve as a protective mechanism against MG-induced neurotoxicity.
- Subjects
GLYOXALASE; ASTROCYTES; METHYL groups; ADVANCED glycation end-products; NEURODEGENERATION; CARBONYL compounds; NEURONS; NEUROTOXICOLOGY
- Publication
Journal of Neuroscience, 2011, Vol 31, Issue 50, p18338
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1249-11.2011