, Volume 23, Issue 6, pp 329-335
Date: 03 Feb 2008

ATP depletion is the major cause of MPP+ induced dopamine neuronal death and worm lethality in α-synuclein transgenic C. elegans

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Abstract

Objective

To investigate the toxic effect of environmental neurotoxin MPP+ to C. elegans and identify the mechanisms that cause the toxicity.

Methods

Human α-synuclein transgenic C. elegans was used as the animal model, the toxic effect of MPP+ to dopamine (DA) neurons and the lifespan of worms was tested. The worms were feed with OP50 to determine whether ATP increase can rescue the worm from toxicity. ATP level and aberrant protein accumulation were analyzed in the MPP+ treated worms with or without OP50 addition.

Results

We found that MPP+ induced DA cell death and worm lethality, which could be prevented by OP50 treatment. OP50 exerted the protective effect by up-regulating ATP level, even though it also induced accumulation of α-synuclein. Despite the undefined role of protein aggregation to the cell death, our results showed that the toxicity of MPP+ was mainly caused by the ATP depletion in the α-synuclein transgenic C. elegans.

Conclusion

MPP+ could induce DA neuronal death and worm lethality in α-synuclein transgenic C. elegans; Compared with the aggregation of α-synuclein, the major cause of MPP+ toxicity appeared due to ATP depletion.

摘要

目的

揭示环境神经毒素 MPP+ 对线虫的毒性影响并探讨其毒性机理。

方法

以人源 α-synuclein 转基因线虫作为动物模型, 用 MPP+ 处理该线虫, 观察 MPP+ 对线虫多巴胺能神经元和其生存能力的影响。 通过供给 OP50 以提高线虫体内 ATP 的水平, 对比分析 ATP 水平、 蛋白质异常沉积等重要指标, 探讨二者在 MPP+ 引起的转基因线虫的病变中所起的作用。

结果

MPP+ 能够引起线虫多巴胺能神经元和线虫虫体的死亡; 尽맜进食 OP50 也会引起 α-synuclein 的沉积, 但进食 OP50 能够提高体内 ATP 的水平并缓解 MPP+ 的毒性。 虽无直接证据证明 α-synuclein 沉积对神经细胞的影响, 但结果提示, 在该转基因线虫中, 与蛋白质的异常沉积相比, MPP+ 导致的 ATP 损耗是其毒性作用的最主要诱因。

结论

MPP+ 可以引起 α-synuclein 转基因线虫多巴胺能神经元的死亡和虫体的死亡, 其毒性的主要原因是 ATP 损耗而不是 α-synuclein 的异常聚集 (沉积)。