Glial cell-derived neurotrophic factor protects against proteasome inhibition-induced dopamine neuron degeneration by suppression of endoplasmic reticulum stress and caspase-3 activation
Glial cell-derived neurotrophic factor protects against proteasome inhibition-induced dopamine neuron degeneration by suppression of endoplasmic reticulum stress and caspase-3 activation
复制标题
胶质细胞源性神经营养因子通过抑制内质网应激和 caspase-3 激活来防止蛋白酶体抑制诱导的多巴胺神经元变性。
DOI：
10.1093/gerona/62.9.943
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发表时间：
2007-09-01
影响因子：
5.1
通讯作者：
Le, Weidong
中科院分区：
文献类型：
--
作者：
Li, Xuping;Peng, Changgeng;Le, Weidong
有证据表明，泛素蛋白酶体系统（UPS）的损伤在帕金森病（PD）多巴胺（DA）神经元变性中起重要作用。有报道称，蛋白酶体抑制剂lactacystin在腹侧中脑（VM）培养中的应用可引起DA神经元变性，尽管其潜在机制尚不清楚。在此，我们使用乳胱氨酸诱导的DA细胞变性模型来研究胶质细胞源性神经营养因子（GDNF）在VM培养中的神经保护作用。我们测量了内质网应激（ERS）相关基因的表达，并确定了caspase-3激活，凋亡细胞死亡，以及在DA神经元中的α-突触核蛋白阳性包涵体。我们发现，GDNF治疗显着抑制ERS相关基因的表达，抑制caspase-3的激活和凋亡细胞死亡，而不影响DA神经元中的α-突触核蛋白阳性夹杂物。我们的研究表明GDNF对UPS损伤模型中DA神经变性的保护作用与ERS和caspase-3抑制有关。
Evidence has shown that ubiquitin proteasome system (UPS) impairment plays an important role in the dopamine (DA) neurodegeneration in Parkinson's disease (PD). It has been reported that application of proteasomal inhibitor lactacystin in ventral mesencephalon (VM) cultures can cause DA neurodegeneration, although the underlying mechanisms are not clear. Herein, we used the lactacystin-induced DA cell degeneration model to study the neuroprotection of glial cell-derived neurotrophic factor (GDNF) in VM cultures. We measured the expression of endoplasmic reticulum stress (ERS)-related genes, and determined the caspase-3 activation, apoptotic cell death, as well as alpha-synuclein-positive inclusions in DA neurons. We found that GDNF treatment significantly suppressed the expression of ERS-related genes and inhibited the activation of caspase-3 and apoptotic cell death without affecting alpha-synuclein-positive inclusions in DA neurons. Our study suggests that the protection of GDNF against DA neurodegeneration in the UPS impairment model is associated with ERS and caspase-3 suppression.