The neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes a Parkinson’s disease (PD)-like syndrome by inducing degeneration of nigrostriatal dopaminergic neurons. Studies of the MPTP model have revealed the pathomechanisms underlying dopaminergic neurodegeneration and facilitated the development of drug treatments for PD. In this review, we provide an update on MPTP bioactivation and biodistribution, reconcile the distinct views on energetic failure versus reactive oxygen species (ROS) formation as main drivers of MPTP-induced neurodegeneration, and describe recently identified intrinsic features of the nigrostriatal system that make it particularly vulnerable to MPTP. We discuss these new perspectives on the endogenous tipping points of tissue homeostasis and the drivers responsible for vicious cycles in relation to their relevance for the development of novel intervention strategies for PD.

神经毒物1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）通过诱导黑质纹状体多巴胺能神经元变性引起帕金森氏病（PD）样综合征。对MPTP模型的研究揭示了多巴胺能神经退行性病变的发病机制，并促进了PD药物治疗的发展。在这篇综述中，我们提供了MPTP生物激活和生物分布的最新信息，调和了关于能量衰竭与活性氧（ROS）形成的不同观点，这些观点是MPTP诱导的神经变性的主要驱动力，并描述了最近发现的黑质纹状体系统的固有特征它特别容易受到MPTP的攻击。