Characterization of chronic low-level proteasome inhibition on neural homeostasis
Characterization of chronic low-level proteasome inhibition on neural homeostasis
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DOI：
10.1046/j.1471-4159.2003.01885.x
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发表时间：
2003-07-01
影响因子：
4.7
通讯作者：
Keller, JN
中科院分区：
文献类型：
--
作者：
Ding, QX;Dimayuga, E;Keller, JN
越来越多的证据表明，蛋白酶体抑制在促进在多种疾病中观察到的神经变性和神经元死亡中起因果作用，包括阿尔茨海默病（AD）和帕金森病（PD）。蛋白酶体功能的严重和急性抑制诱导神经元死亡和神经病理学的能力与AD和PD中观察到的相似，这一点已得到充分证实。然而，目前慢性低水平蛋白酶体抑制对神经稳态的影响尚未阐明。为了确定慢性低水平蛋白酶体抑制对神经稳态的影响，我们在连续暴露于低浓度（100 nm）的蛋白酶体抑制剂MG 115后分离的神经SH-SY 5 Y细胞的单个集落中进行了研究。克隆细胞系出现形态相似的控制文化，但表现出显着不同的增殖和分化率。在克隆细胞系中观察到蛋白质氧化和蛋白质不溶性水平升高，所有克隆细胞系对血清戒断和氧化应激诱导的神经死亡更具抗性。有趣的是，克隆细胞系表现出增加的大自噬的证据，表明慢性低水平蛋白酶体抑制可能导致溶酶体系统的过度激活。两者合计，这些数据表明，慢性低水平蛋白酶体抑制对神经内稳态有多种影响，并表明，研究慢性低水平蛋白酶体抑制的影响可能有助于了解AD和PD中蛋白质氧化，蛋白质不溶性，蛋白酶体功能，巨自噬和神经活力之间的关系。
Increasing evidence suggests that proteasome inhibition plays a causal role in promoting the neurodegeneration and neuron death observed in multiple disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). The ability of severe and acute inhibition of proteasome function to induce neuron death and neuropathology similar to that observed in AD and PD is well documented. However, at present the effects of chronic low-level proteasome inhibition on neural homeostasis has not been elucidated. In order to determine the effects of chronic low-level proteasome inhibition on neural homeostasis, we conducted studies in individual colonies of neural SH-SY5Y cells that were isolated following continual exposure to low concentrations (100 nm) of the proteasome inhibitor MG115. Clonal cell lines appeared morphologically similar to control cultures but exhibited significantly different rates of both proliferation and differentiation. Elevated levels of protein oxidation and protein insolubility were observed in clonal cell lines, with all clonal cell lines being more resistant to neural death induced by serum withdrawal and oxidative stress. Interestingly, clonal cell lines demonstrated evidence for increased macroautophagy, suggesting that chronic low-level proteasome inhibition may cause an excessive activation of the lysosomal system. Taken together, these data indicate that chronic low-level proteasome inhibition has multiple effects on neural homeostasis, and suggests that studying the effects of chronic low-level proteasome inhibition may be useful in understanding the relationship between protein oxidation, protein insolubility, proteasome function, macroautophagy and neural viability in AD and PD.