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First published on November 23, 2005; DOI: 10.1124/mol.105.016675

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Received for publication July 14, 2005.
Revised November 23, 2005.
Accepted for publication November 23, 2005.

Heme Deficiency is Associated with Senescence and Causes Suppression of NMDA Receptor Subunits Expression in Primary Cortical Neurons

Tatyana Chernova 1*, Pierluigi Nicotera 2, Andrew G. Smith 2

1 Leicester University 2 University of Leicester

* Address correspondence to: E-mail: tc28{at}le.ac.uk

Abstract

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 senescence of 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 (NMDA{zeta}1 and {epsilon}2) and neurofilament light peptide (NF-L) were found to be characteristic of the aging process as reported in vivo. 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 implicating depletion of a regulatory heme pool. Inhibition of heme synthesis (by 70-80%) at different enzymic steps by succinyl acetone (SA) and N-methylprotoporphyrin IX (NMP) resulted in the earlier lowered expression of NMDA{zeta}1 and {epsilon}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 Fechm1Pas mutant mice demonstrating depressed heme synthesis showed premature senescence and reduced expression of NMDA{zeta}1 and {epsilon}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.


Key words: Glutamate, Regulation - physiological, Heme metabolism, Excitotoxicity, neurodegeneration


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