Heme deficiency is associated with senescence and causes suppression of N-methyl-D-aspartate receptor subunits expression in primary cortical neurons.
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 (NMDAzeta1 and -epsilon2) 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; Brain Res Mol Brain Res 99:40-45, 2002). 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 NMDAzeta1 and -epsilon2 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 NMDAzeta1 and -epsilon2 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.
Chernova
Tatyana
T
MRC Toxicology Unit, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK. tc28@le.ac.uk
Nicotera
Pierluigi
P
Smith
Andrew G
AG
D000624:5-Aminolevulinate Synthetase / Q000235:genetics; D000818:Animals; D056668:Cathepsin L; D002403:Cathepsins / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D002540:Cerebral Cortex / Q000166:cytology; D003546:Cysteine Endopeptidases / Q000235:genetics; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006418:Heme / Q000172:deficiency* / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics; D006427:Hemin / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D015854:Up-Regulation
D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D006418:Heme; D006427:Hemin; D051547:Heme Oxygenase-1; D000624:5-Aminolevulinate Synthetase; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C534278:Ctsl protein, mouse