Aging is associated with dimerization and inactivation of the brain-enriched tyrosine phosphatase STEP.
Aging is associated with dimerization and inactivation of the brain-enriched tyrosine phosphatase STEP.
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DOI：
10.1016/j.neurobiolaging.2016.02.004
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发表时间：
2016-05
影响因子：
4.2
通讯作者：
Paul S
中科院分区：
文献类型：
--
作者：
Rajagopal S;Deb I;Poddar R;Paul S
纹状体富含酪氨酸磷酸酶 (STEP) 涉及多种与氧化应激相关的年龄相关神经系统疾病的病因，并且还已知通过调节谷氨酸能传递在神经保护中发挥作用。然而，衰老对大脑中 STEP 水平和活动的可能影响仍不清楚。在这项研究中，使用年轻（1 个月）、成年（4 个月）和老年（18 个月）大鼠，我们发现衰老与二聚化的增加和 STEP 活性的丧失有关。 STEP 二聚化的增加主要在皮层和海马体中观察到，并且与还原型谷胱甘肽和总谷胱甘肽水平的消耗相关，表明氧化应激增加。与此解释一致的是，谷胱甘肽消耗和氧化应激的细胞培养模型中的研究也证明了STEP二聚体和高阶寡聚体的形成，其中涉及多个半胱氨酸残基之间的分子间二硫键形成。相反，给予 N-乙酰半胱氨酸（一种增强谷胱甘肽生物合成的主要抗氧化剂）会减弱皮层和海马中的 STEP 二聚化。研究结果表明，随着年龄依赖性氧化应激的增加，这种内在保护反应途径的丧失可能是大脑对与年龄相关的神经系统疾病易感性的一个促成因素。
The striatal-enriched tyrosine phosphatase (STEP) is involved in the etiology of several age-associated neurological disorders linked to oxidative stress and is also known to play a role in neuroprotection by modulating glutamatergic transmission. However, the possible effect of aging on STEP level and activity in the brain is still unclear. In this study, using young (1 month), adult (4 month) and aged (18 month) rats we show that aging is associated with increase in dimerization and loss of activity of STEP. Increased dimerization of STEP is primarily observed in the cortex and hippocampus and is associated with depletion of both reduced and total glutathione levels, suggesting an increase in oxidative stress. Consistent with this interpretation studies in cell culture models of glutathione depletion and oxidative stress also demonstrates formation of dimers and higher order oligomers of STEP that involves intermolecular disulfide bond formation between multiple cysteine residues. Conversely, administration of N-acetyl cysteine, a major antioxidant that enhances glutathione biosynthesis, attenuates STEP dimerization both in the cortex and hippocampus. The findings indicate that loss of this intrinsic protective response pathway with age-dependent increase in oxidative stress may be a contributing factor for the susceptibility of the brain to age-associated neurological disorders.