Different dopaminergic (DA) neuronal subgroups exhibit distinct vulnerability to stress, while the underlying mechanisms are elusive. Here we report that the transient receptor potential melastatin 2 (TRPM2) channel is preferentially expressed in vulnerable DA neuronal subgroups, which correlates positively with aging in Parkinson’s Disease (PD) patients. Overexpression of human TRPM2 in the DA neurons of C. elegans resulted in selective death of ADE but not CEP neurons in aged worms. Mechanistically, TRPM2 activation mediates FZO-1/CED-9-dependent mitochondrial hyperfusion and mitochondrial permeability transition (MPT), leading to ADE death. In mice, TRPM2 knockout reduced vulnerable substantia nigra pars compacta (SNc) DA neuronal death induced by stress. Moreover, the TRPM2-mediated vulnerable DA neuronal death pathway is conserved from C. elegans to toxin-treated mice model and PD patient iPSC-derived DA neurons. The vulnerable SNc DA neuronal loss is the major symptom and cause of PD, and therefore the TRPM2-mediated pathway serves as a promising therapeutic target against PD.

不同的多巴胺能（DA）神经元亚群对压力表现出不同的脆弱性，而潜在的机制却难以捉摸。在这里，我们报道瞬态受体电位褪黑素 2 (TRPM2) 通道优先在脆弱的 DA 神经元亚群中表达，这与帕金森病 (PD) 患者的衰老呈正相关。线虫DA 神经元中人类 TRPM2 的过度表达导致衰老线虫中 ADE 选择性死亡，但不导致 CEP 神经元选择性死亡。从机制上讲，TRPM2 激活介导 FZO-1/CED-9 依赖性线粒体过度灌注和线粒体通透性转变 (MPT)，导致 ADE 死亡。在小鼠中，TRPM2 敲除减少了应激引起的脆弱黑质致密部 (SNc) DA 神经元死亡。此外，TRPM2 介导的脆弱 DA 神经元死亡途径从线虫到毒素处理的小鼠模型和 PD 患者 iPSC 衍生的 DA 神经元都是保守的。脆弱的 SNc DA 神经元损失是 PD 的主要症状和原因，因此 TRPM2 介导的通路可作为 PD 的有前途的治疗靶点。