Multiple aspects of homocysteine neurotoxicity: Glutamate excitotoxicity, kinase hyperactivation and DNA damage
Multiple aspects of homocysteine neurotoxicity: Glutamate excitotoxicity, kinase hyperactivation and DNA damage
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DOI：
10.1002/jnr.10416
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发表时间：
2002-12-01
影响因子：
4.2
通讯作者：
Shea, TB
中科院分区：
文献类型：
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作者：
Ho, PI;Ortiz, D;Shea, TB
同型半胱氨酸（HC）是一种神经毒性氨基酸，在包括阿尔茨海默病（AD）在内的几种神经系统疾病中积累。我们研究了培养的小鼠皮层神经元与HC治疗的后果。同型半胱氨酸诱导的细胞溶质钙、活性氧、磷酸化tau免疫反应性和外化磷脂酰丝氨酸（指示细胞凋亡）增加。同型半胱氨酸诱导的钙内流通过NMDA通道激活，刺激谷氨酸兴奋性毒性，证明了治疗与NMDA通道和代谢型谷氨酸受体的拮抗剂，分别。NMDA通道拮抗剂MK-801减少tau蛋白磷酸化，但HC处理后不凋亡，表明HC介导的凋亡不是由于钙内流。HC处理后的细胞凋亡通过与聚ADP核糖体聚合酶（PARP）抑制剂3-氨基苯并嘧啶（3ab）共同处理而减少，这与之前的报道一致，即PARP介导的DNA链断裂修复介导的HC诱导的细胞凋亡引起的ATP耗竭。然而，用3ab处理并没有减少tau磷酸化，因此tau的过度磷酸化可能不会在这些条件下促进HC诱导的细胞凋亡。通过与激酶抑制剂PD 98059共同治疗来抑制促分裂原活化蛋白激酶抑制HC治疗后的tau磷酸化，但不抑制凋亡。HC积累降低细胞水平的S-腺苷甲硫氨酸（SAM）;与SAM共治疗减少细胞凋亡，这表明抑制关键的甲基化反应可能介导HC诱导的细胞凋亡。这些研究结果表明，HC损害神经元的稳态多，不同的路线。(C)2002 Wiley-Liss，Inc.
Homocysteine (HC) is a neurotoxic amino acid that accumulates in several neurological disorders including Alzheimer's disease (AD). We examined the consequences of treatment of cultured murine cortical neurons with HC. Homocysteine-induced increases in cytosolic calcium, reactive oxygen species, phospho-tau immunoreactivity and externalized phosphatidyl serine (indicative of apoptosis). Homocysteine-induced calcium influx through NMDA channel activation, which stimulated glutamate excitotoxicity, as evidenced by treatment with antagonists of the NMDA channel and metabotropic glutamate receptors, respectively. The NMDA channel antagonist MK-801 reduced tau phosphorylation but not apoptosis after HC treatment, suggesting that HC-mediated apoptosis was not due to calcium influx. Apoptosis after HC treatment was reduced by co-treatment with 3-aminobenazmidine (3ab), an inhibitor of poly-ADP-ribosome polymerase (PARP), consistent with previous reports that ATP depletion by PARP-mediated repair of DNA strand breakage mediated HC-induced apoptosis. Treatment with 3ab did not reduce tau phosphorylation, however, therefore hyperphosphorylation of tau may not contribute to HC-induced apoptosis under these conditions. Inhibition of mitogen-activated protein kinase by co-treatment with the kinase inhibitor PD98059 inhibited tau phosphorylation but not apoptosis after HC treatment. HC accumulation reduces cellular levels of S-adenosyl methionine (SAM); co-treatment with SAM reduced apoptosis, suggesting that inhibition of critical methylation reactions may mediate HC-induced apoptosis. These findings indicate that HC compromises neuronal homeostasis by multiple, divergent routes. (C) 2002 Wiley-Liss, Inc.