香港中文大学朱宝亭近日取得一项新成果。研究提出了神经毒物（MPTP和6-羟基多巴胺）和α-突触核蛋白诱导帕金森病的致病机制：一个统一的假说。2025年11月19日，国际知名学术期刊《分子细胞生物学报》发表了这一成果。

帕金森氏病（PD）中多巴胺能神经元选择性丧失的机制目前尚不清楚。MPTP是一种非法药物污染物，可选择性地诱发人和动物帕金森病，与特发性帕金森病非常相似。与MPTP一样，6-羟多巴胺（6-OHDA）是另一种在动物模型中也能选择性诱导帕金森病的神经毒物。本文提出了一个统一的假说，为MPTP和6-OHDA诱导帕金森病的发病机制提供了一个合理的解释。

该假说有三个核心要素：(1)囊泡单胺转运蛋白2 （VMAT2）是负责错置的胞质多巴胺（DA）的反向转运（外排）的转运蛋白。（2）VMAT2介导的DA逆向运输的激活是由氧化应激升高引起的，通常是由多巴胺能神经元中胞质DA的积累引起的。（3） VMAT2是MPP⁺ （MPTP的一种有毒代谢物）和6-OHDA的主要靶点，MPP⁺或6-OHDA抑制VMAT2介导的DA逆向运输将导致胞质DA的积累，其随后的氧化/自氧化将进一步加剧氧化应激并产生化学反应性的神经毒性DA衍生物。这些与多巴胺相关的氧化变化共同促进多巴胺能神经元的选择性损伤和帕金森病的诱导。这一机械性假设与大量实验观察结果相一致，也为许多实验发现提供了机械性解释。此外，基于α-突触核蛋白在多巴胺能神经元中抑制VMAT2介导的DA反向转运的强大能力，这一假说为α-突触核蛋白在人PD中的致病作用提供了机制见解。

附：英文原文

Title: Pathogenic Mechanism Underlying Parkinsonism Induced by Neurotoxicants (MPTP and 6-Hydroxydopamine) and α-Synuclein: A Unifying Hypothesis

Author: Zhu, Bao Ting

Issue&Volume: 2025-11-19

Abstract: The mechanism underlying the selective loss of dopaminergic neurons in Parkinson’s disease (PD) is still not understood at present. MPTP, an illicit drug contaminant, can selectively induce parkinsonism in humans and animals which is very similar to idiopathic PD. Like MPTP, 6-hydroxydopamine (6-OHDA) is another neurotoxicant also capable of selectively inducing parkinsonism in animal models. In this paper, a unifying hypothesis is proposed, which offers a plausible explanation for the pathogenic mechanism of parkinsonism induced by MPTP and 6-OHDA. This hypothesis has three core elements: (i) The vesicular monoamine transporter 2 (VMAT2) is the transporter responsible for the reverse transport (efflux) of the misplaced cytosolic dopamine (DA). (ii) Activation of VMAT2-mediated DA reverse transport is caused by elevated oxidative stress, often resulting from the buildup of cytosolic DA in dopaminergic neurons. (iii) VMAT2 is a major target of MPP+ (a toxic metabolite of MPTP) and 6-OHDA, and inhibition of VMAT2-mediated DA reverse transport by MPP+ or 6-OHDA will result in the buildup of cytosolic DA, and its subsequent oxidation/auto-oxidation will further heighten oxidative stress and generate chemically-reactive, neurotoxic DA derivatives. These DA-associated oxidative changes jointly contribute to the selective injury to dopaminergic neurons and the induction of parkinsonism. This mechanistic hypothesis agrees with a large body of experimental observations, and also offers a mechanistic explanation for many experimental findings. Additionally, this hypothesis offers mechanistic insights into the pathogenic role of α-synuclein in human PD based on its strong ability to suppress VMAT2-mediated DA reverse transport in dopaminergic neurons.

DOI: 10.1093/jmcb/mjaf041

Source: https://academic.oup.com/jmcb/advance-article/doi/10.1093/jmcb/mjaf041/8327621searchresult=1