Multiple molecular pathways are involved in the neuroprotection of GDNF against proteasome inhibitor induced dopamine neuron degeneration in vivo
Multiple molecular pathways are involved in the neuroprotection of GDNF against proteasome inhibitor induced dopamine neuron degeneration in vivo
复制标题
多种分子途径参与 GDNF 对体内蛋白酶体抑制剂诱导的多巴胺神经元变性的神经保护。
DOI：
10.3181/0712-rm-329
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发表时间：
2008-07-01
影响因子：
3.2
通讯作者：
Le, Weidong
中科院分区：
文献类型：
--
作者：
Du, Yunlan;Li, Xuping;Le, Weidong
泛素-蛋白酶体系统（UPS）受损是帕金森病（PD）神经退行性变的细胞机制。胶质细胞源性神经营养因子（GDNF）是促进中脑多巴胺（DA）神经元生长和存活的最有效的神经营养因子之一。为了研究GDNF在UPS损伤诱导的PD模型中是否具有神经保护作用，我们在C57 BL/6小鼠黑质纹状体损伤后通过立体定向注射蛋白酶体抑制剂lactacystin在中前脑束中通过渗透泵给予GDNF。我们发现，lactacystin注射严重损伤黑质DA神经元，并降低纹状体DA及其代谢产物的水平，而持续中等剂量的GDNF延长给药两周可显著减轻lactacystin诱导的黑质DA神经元和纹状体DA水平的损失，分别为31%和40%。我们还研究了GDNF的神经保护作用的分子机制，表明lactacystin给药可引起细胞外信号调节激酶（ERK）、p38 MAPK（p38）和c-Jun N-末端激酶（JNK）的磷酸化，而GDNF治疗可进一步增强ERK和Akt的磷酸化，但降低JNK和p38的水平。这些结果表明，GDNF长期处理可以保护黑质DA神经元免受UPS损伤诱导的变性。p38、JNK、Akt和ERK等信号通路在GDNF的神经保护作用中起重要作用。
The impairment of ubiquitin-proteasome system (UPS) is a cellular mechanism underlying the neurodegenerative process in Parkinson's disease (PD). Glial cell line-derived neurotrophic factor (GDNF) is one of the most potent neurotrophic factors promoting the growth and survival of mesencephalic dopamine (DA) neurons. To investigate whether GDNF has neuroprotective effects in a PD model induced by UPS impairment we administered GDNF by osmotic pump in C57BL/6 mice after nigrostriatal lesions with stereotactic injection of proteasome inhibitor lactacystin in the middle forebrain bundle. We found that lactacystin injection severely injured the nigral DA neurons and reduced the striatal levels of DA and its metabolites, while prolonged administration of GDNF at a sustained moderate dose for two weeks can significantly attenuate the lactacystin-induced loss of nigral DA neurons and striatal DA levels by 31% and 40%, respectively. We also investigated the molecular mechanisms for the neuroprotective effects of GDNF showing that lactacystin administration can cause the phosphorylation of extracellular signal-regulated kinase (ERK), p38MAPK (p38), and the c-Jun N-terminal kinase (JNK), whereas GDNF treatment can further enhance the phosphorylation of ERK and Akt but reduce the levels of JNK and p38. These results indicate that prolonged treatment with GDNF can protect the nigral DA neurons from the UPS impairment-induced degeneration. Several signaling pathways including p38, JNK, Akt and ERK molecules seem to play an important role in this neuroprotection by GDNF.