Heme deficiency is associated with senescence and causes suppression of N-methyl-D-aspartate receptor subunits expression in primary cortical neurons
Heme deficiency is associated with senescence and causes suppression of N-methyl-D-aspartate receptor subunits expression in primary cortical neurons
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DOI：
10.1124/mol.105.016675
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发表时间：
2006-03-01
影响因子：
3.6
通讯作者：
Smith, AG
中科院分区：
文献类型：
--
作者：
Chernova, T;Nicotera, P;Smith, AG
血红素是许多药理学和毒理学过程的重要组成部分，研究表明，血红素缺乏可能在细胞衰老中发挥作用。采用BALB/c小鼠原代皮层神经元长期培养建立了神经元老化模型。老年神经元表现出衰老表型和组织蛋白酶-L表达的显着上调。发现N-甲基-D-天冬氨酸（NMDA）受体亚基（NMDA ζ 1和NMDA 2）和神经丝轻肽（NF-L）的候选神经元特异性基因的下调是体内报道的衰老过程的特征（Brain Res 907：71-83，2001; Brain Res Mol Brain Res 99：40-45，2002）。相反，血红素合成和降解（5-氨基乙酰丙酸合酶1和血红素加氧酶1，分别）的控制酶的基因上调，这意味着监管血红素池的耗尽。琥珀酰丙酮和N-甲基原卟啉IX在不同的酶促步骤抑制血红素合成（70-80%）导致NMDA zeta 1和NF-L的表达较早降低。将外源性氯化血红素添加到血红素耗尽的细胞中拯救了这些神经元特异性基因的表达。与野生型细胞相比，BALB/c Fech（m1 Pas）突变小鼠的皮层神经元培养显示血红素合成受抑制，表现出早衰和NMDA zeta 1和-NF 2受体亚基和NF-L表达减少。我们的研究结果表明，减少与衰老相关的神经元中血红素的可用性可能对突触功能有显着影响。
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 (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 (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 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 Fech(m1Pas) 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.