Differential sensitivity of oligodendrocytes and motor neurons to reactive nitrogen species: implications for multiple sclerosis.
Differential sensitivity of oligodendrocytes and motor neurons to reactive nitrogen species: implications for multiple sclerosis.
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DOI：
10.1111/j.1471-4159.2009.05891.x
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发表时间：
2009-04
影响因子：
4.7
通讯作者：
Estévez AG
中科院分区：
文献类型：
--
作者：
Bishop A;Hobbs KG;Eguchi A;Jeffrey S;Smallwood L;Pennie C;Anderson J;Estévez AG
一氧化氮 (NO) 具有有益作用或毒性作用，具体取决于其浓度。在病理条件下，NO 与超氧化物反应形成过氧亚硝酸盐，后者硝酸化蛋白质形成硝基酪氨酸残基 (3NY)，导致蛋白质功能丧失、信号转导扰乱和细胞死亡。 3NY 免疫反应性存在于许多中枢神经系统疾病中，特别是多发性硬化症 (MS)。在这里，使用高通量NO供体精胺NONOate，我们报告少突胶质细胞对NO有抵抗力，而运动神经元对NO敏感。运动神经元敏感性与 NO 依赖性 3NY 形成相关，与少突胶质细胞相比，3NY 在运动神经元中更为明显，表明过氧亚硝酸盐是有毒分子。血红素代谢酶血红素加氧酶 1 (HO-1) 是少突胶质细胞 NO 抵抗所必需的，HO1 抑制后抵抗力丧失就证明了这一点。尿酸清除过氧亚硝酸盐可恢复抵抗力，进一步表明过氧亚硝酸盐是 NO 敏感性的原因。最重要的是，原代少突胶质细胞和运动神经元的培养物中也存在对 NO 的不同敏感性。最后，与少突胶质细胞或少突胶质细胞条件培养基共培养的运动神经元变得对一氧化氮毒性具有抵抗力。初步研究表明少突胶质细胞释放一种可保护运动神经元的可溶性因子。我们的研究结果挑战了当前少突胶质细胞是多发性硬化症病理学唯一目标的观念。
Depending on its concentration, nitric oxide (NO) has beneficial or toxic effects. In pathological conditions, NO reacts with superoxide to form peroxynitrite, which nitrates proteins forming nitrotyrosine residues (3NY), leading to loss of protein function, perturbation of signal transduction, and cell death. 3NY immunoreactivity is present in many CNS diseases, particularly Multiple Sclerosis (MS). Here, using the high flux NO donor, spermine NONOate, we report that oligodendrocytes are resistant to NO, while motor neurons are NO sensitive. Motor neuron sensitivity correlates with the NO-dependent formation of 3NY, which is significantly more pronounced in motor neurons as compared to oligodendrocytes, suggesting peroxynitrite as the toxic molecule. The heme-metabolizing enzyme, heme-oxygenase-1 (HO-1), is necessary for oligodendrocyte NO resistance, as demonstrated by loss of resistance after HO1 inhibition. Resistance is reinstated by peroxynitrite scavenging with uric acid further implicating peroxynitrite as responsible for NO sensitivity. Most importantly, differential sensitivity to NO is also present in cultures of primary oligodendrocytes and motor neurons. Finally, motor neurons cocultured with oligodendrocytes, or oligodendrocyte-conditioned media, become resistant to NO toxicity. PRELIMINARY STUDIES SUGGEST OLIGODENDROCYTES RELEASE A SOLUBLE FACTOR THAT PROTECTS MOTOR NEURONS. Our findings challenge the current paradigm that oligodendrocytes are the exclusive target of MS pathology.
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影响因子：
4.4
作者：
Bizzozero, O;DeJesus, G;Pastuszyn, A
通讯作者：
Pastuszyn, A
DOI：
10.1016/j.bbrc.2004.10.010
发表时间：
2004-12-03
影响因子：
3.1
作者：
Bishop, A;Yet, SF;Demple, B
通讯作者：
Demple, B
DOI：
10.1023/a:1027324230923
发表时间：
2003-01-01
期刊：
JOURNAL OF NEUROCYTOLOGY
影响因子：
--
作者：
Buntinx, M;Vanderlocht, J;Steels, P
通讯作者：
Steels, P
影响因子：
3.1
作者：
Cornish, AS;Jijon, H;Madsen, KL
通讯作者：
Madsen, KL
影响因子：
7.4
作者：
Estévez, AG;Sampson, JB;Beckman, JS
通讯作者：
Beckman, JS