甲基苯丙胺（METH）中毒可致神经退行性病变。以帕金森病(PD)为代表的神经退行性病变中，神经突触重要分子α-突触核蛋白（α-Syn）异常修饰、折叠及堆积，形成特征性病变Lewy小体并导致神经元结构功能损害。本人在前期研究中发现，METH作用后α-Syn表达显著增高，但真正引起α-Syn异常修饰、聚集及清除的机制不明。研究显示PD中糖原合成酶激酶3β（GSK3β）表达升高，且能与α-Syn形成复合体调节下游微管稳定性；PD中神经元溶酶体葡糖脑苷脂酶（GCase）活性减低而α-Syn累积，从而导致溶酶体功能紊乱。因此我们推断：METH可能通过干扰GSK3β/α-Syn/GCase代谢通路，导致α-Syn异常折叠聚集、细胞骨架破坏以及溶酶体功能紊乱，最后引起神经退行性病变。本研究拟通过尸检材料、动物及细胞实验证实上述推断，以期为METH神经毒性机制及寻找戒毒药物靶点提供理论基础。

Methamphetamine (METH) can cause neurodegeneration. In typical neurodegeneration disorders such as Pakinson Disease (PD), key neural synapse molecule α-Synuclein (α-Syn) are modified, folded and accumulated abnormally to form unique pathological lesion of Lewy body, which is harmful for neural structure and function. My previous results show that there are significant upregulations of α-Syn after METH treatment, but the underlying mechanisms for α-Syn modification, accumulation and clearance are unclear. It is shown that the expression of glycogen synthetase kinase 3β (GSK3β) is increased and can form complex with α-Syn to regulate microtubule stability in PD. Moreover, the activity of glucocerebrosidase (GCase) has decreased but α-Syn accumulated, which leads to dysfunctional lysosome. We therefore hypothesize that METH disrupts GSK3β/α-Syn/GCase metabolic pathway and leads to α-Syn abnormal accumulation, cytoskeleton damage, lysosomal impairment and finally neurodegeneration. We will use samples from autopsy, animal model and cell assays to predict this hypothesis, and our results will provide new theory basis for exploration the mechanism of METH neurotoxicity and new targets for rehabilitation.