β-synuclein regulates Akt activity in neuronal cells -: A possible mechanism for neuroprotection in Parkinson's disease
β-synuclein regulates Akt activity in neuronal cells -: A possible mechanism for neuroprotection in Parkinson's disease
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DOI：
10.1074/jbc.m313784200
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发表时间：
2004-05-28
影响因子：
4.8
通讯作者：
Masliah, E
中科院分区：
文献类型：
--
作者：
Hashimoto, M;Bar-on, P;Masliah, E
最近的研究表明，路易体形成障碍(如帕金森病和路易体痴呆)的神经退变过程与α-突触核蛋白的积聚有关，并且β-突触核蛋白可能保护中枢神经系统免受α-突触核蛋白的神经毒性作用。然而，其机制尚不清楚。本研究的主要目的是探讨丝氨酸苏氨酸激酶Akt(又称蛋白激酶B)信号通路在β-突触核蛋白神经保护机制中的作用。为此，我们分析了突触核蛋白转基因的B103神经母细胞瘤细胞和原代皮质神经元的Akt活性和细胞存活率。β-突触核蛋白转染组Akt活性增强，对鱼藤酮的神经毒性作用有保护作用。Akt表达下调导致对鱼藤酮毒性的易感性增加，而转导编码β-突触核蛋白的慢病毒载体则具有保护作用。β-突触核蛋白对Akt通路的影响似乎是通过这些分子之间的直接相互作用实现的，并且不依赖于上游信号分子。综上所述，这些结果表明，β-突触核蛋白的神经保护机制可能涉及β-突触核蛋白和Akt之间的直接相互作用，并表明该信号通路可能成为治疗与帕金森综合征和α-突触核蛋白聚集相关的神经系统疾病的潜在靶点。
Recent studies have shown that the neurodegenerative process in disorders with Lewy body formation, such as Parkinson's disease and dementia with Lewy bodies, is associated with alpha-synuclein accumulation and that beta-synuclein might protect the central nervous system from the neurotoxic effects of alpha-synuclein. However, the mechanisms are unclear. The main objective of the present study was to investigate the potential involvement of the serine threonine kinase Akt ( also known as protein kinase B) signaling pathway in the mechanisms of beta-synuclein neuroprotection. For this purpose, Akt activity and cell survival were analyzed in synuclein-transfected B103 neuroblastoma cells and primary cortical neurons. beta-Synuclein transfection resulted in increased Akt activity and conferred protection from the neurotoxic effects of rotenone. Down-regulation of Akt expression resulted in an increased susceptibility to rotenone toxicity, whereas transfection with a lentiviral vector encoding for beta-synuclein was protective. The effects of beta-synuclein on the Akt pathway appear to be by direct interaction between these molecules and were independent of upstream signaling molecules. Taken together, these results indicate that the mechanisms of beta-synuclein neuroprotection might involve direct interactions between beta-synuclein and Akt and suggest that this signaling pathway could be a potential therapeutic target for neurological conditions associated with parkinsonism and alpha-synuclein aggregation.