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Heme Deficiency Is Associated with Senescence and Causes Suppression of N-Methyl-D-aspartate Receptor Subunits Expression in Primary Cortical Neurons

Medical Research Council Toxicology Unit, University of Leicester, Leicester, United Kingdom

Heme is a crucial component of many pharmacological and toxicological processes, and studies have suggested that heme deficiency may play a role in cellular ageing. A model of ageing neurons was established using prolonged cultures of BALB/c mouse primary cortical neurons. Aged neurons displayed a senescent phenotype and a marked up-regulation of cathepsin-L expression. Down-regulation of the candidate neuron-specific genes for N-methyl-D-aspartate (NMDA) receptor subunits (NMDA1 and -2) and neurofilament light peptide (NF-L) were found to be characteristic of the aging process as reported in vivo (Brain Res 907:71-83, 2001[CrossRef][Medline]; Brain Res Mol Brain Res 99:40-45, 2002[Medline]). In contrast, the genes for the controlling enzymes of heme synthesis and degradation (5-aminolevulinate synthase 1 and heme oxygenase 1, respectively) were up-regulated, implying depletion of a regulatory heme pool. Inhibition of heme synthesis (by 70-80%) at different enzymic steps by succinyl acetone and N-methylprotoporphyrin IX resulted in the earlier lowered expression of NMDA1 and -2 and NF-L. Exogenous hemin added to heme-depleted cells rescued the expression of these neuron-specific genes. Culture of cortical neurons from BALB/c Fech^m1Pas mutant mice demonstrating depressed heme synthesis showed premature senescence and reduced expression of NMDA1 and -2 receptor subunits and NF-L compared with wild-type cells. Our findings suggest that reduced availability of heme in neurons associated with senescence may have significant effects on synaptic function.

Address correspondence to: Dr. Tatyana Chernova, MRC Toxicology Unit, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK. E-mail: tc28{at}le.ac.uk

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