Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan.
Global Career Design Center, Hiroshima University, Hiroshima, 739-8514, Japan.
Sci Rep. 2017 Apr 26;7:46668. doi: 10.1038/srep46668.
Parkinson's disease (PD) is a prevalent neurodegenerative disorder, mainly characterised by the progressive loss of dopaminergic neurons. MPP has been widely used as a PD-related neurotoxin, and their reports suggested the several hypotheses for neuronal cell death. However, most of these hypotheses come from the studies about the acute MPP exposure. We previously revealed that mild MPP exposure (10 and 200 μM), which induces gradual cell death, impairs autophagosome degradation at 48 h. In the present study, we further investigated the specific events of mild MPP exposure and revealed that mild MPP exposure causes the cell death through glucose starvation, but not acute toxic model (2.5 and 5 mM). At 36 h after mild MPP exposure, autophagosome synthesis was enhanced owing to glucose starvation and continued to enhance until 48 h, despite impaired autophagosome degradation. Inhibition of autophagosome synthesis reduced mild MPP-induced cell death. In conclusion, we clarified that glucose starvation-enhanced autophagosome synthesis occurs at an earlier stage than impaired autophagosome degradation and is important in mild MPP toxicity.
帕金森病（PD）是一种常见的神经退行性疾病，主要特征是多巴胺能神经元的进行性丧失。MPP 已被广泛用作与 PD 相关的神经毒素，其报告提出了几种神经元细胞死亡的假说。然而，这些假说大多来自于对急性 MPP 暴露的研究。我们之前的研究表明，轻度 MPP 暴露（10 和 200μM）会导致逐渐的细胞死亡，并在 48 小时时损害自噬体的降解。在本研究中，我们进一步研究了轻度 MPP 暴露的具体事件，并揭示了轻度 MPP 暴露会导致细胞死亡是通过葡萄糖饥饿引起的，而不是通过急性毒性模型（2.5 和 5mM）引起的。在轻度 MPP 暴露 36 小时后，由于葡萄糖饥饿，自噬体的合成增强，并持续增强到 48 小时，尽管自噬体的降解受损。自噬体合成的抑制减少了轻度 MPP 诱导的细胞死亡。总之，我们阐明了葡萄糖饥饿增强的自噬体合成发生在自噬体降解受损之前的早期阶段，并且在轻度 MPP 毒性中很重要。
