RT Journal Article
SR Electronic
T1 Heme Deficiency Is Associated with Senescence and Causes Suppression of <em>N</em>-Methyl-<span class="sc">d</span>-aspartate Receptor Subunits Expression in Primary Cortical Neurons
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 697
OP 705
DO 10.1124/mol.105.016675
VO 69
IS 3
A1 Tatyana Chernova
A1 Pierluigi Nicotera
A1 Andrew G. Smith
YR 2006
UL http://molpharm.aspetjournals.org/content/69/3/697.abstract
AB 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 (NMDAζ1 and -ϵ2) and neurofilament light peptide (NF-L) were found to be characteristic of the aging process as reported in vivo (Brain Res907:71-83, 2001OpenUrlCrossRefPubMedWeb of Science; Brain Res Mol Brain Res99:40-45, 2002OpenUrlCrossRefPubMed). 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 NMDAζ1 and -ϵ2 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 Fechm1Pas mutant mice demonstrating depressed heme synthesis showed premature senescence and reduced expression of NMDAζ1 and -ϵ2 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.