TRPM2 as a conserved gatekeeper determines the vulnerability of DA neurons by mediating ROS sensing and calcium dyshomeostasis

IF 6.7 2区 医学 Q1 NEUROSCIENCES Progress in Neurobiology Pub Date : 2023-12-01 DOI:10.1016/j.pneurobio.2023.102530
Peiwu Ye , Qiuyuan Fang , Xupang Hu , Wenjuan Zou , Miaodan Huang , Minjing Ke , Yunhao Li , Min Liu , Xiaobo Cai , Congyi Zhang , Ning Hua , Umar Al-Sheikh , Xingyu Liu , Peilin Yu , Peiran Jiang , Ping-Yue Pan , Jianhong Luo , Lin-Hua Jiang , Suhong Xu , Evandro F. Fang , Wei Yang
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Abstract

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.

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TRPM2作为一个保守的看门人,通过介导ROS传感和钙稳态失调来决定DA神经元的脆弱性。
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,而其潜在机制尚不清楚。在此,我们报道了瞬时受体电位美司他汀2(TRPM2)通道在易受损伤的DA神经元亚群中优先表达,这与帕金森病(PD)患者的衰老呈正相关。人类TRPM2在秀丽隐杆线虫的DA神经元中的过度表达导致老年蠕虫中ADE神经元的选择性死亡,而不是CEP神经元。从机制上讲,TRPM2激活介导FZO-1/CED-9依赖性线粒体超融合和线粒体通透性转变(MPT),导致ADE死亡。在小鼠中,TRPM2敲除减少了应激诱导的脆弱黑质致密部(SNc)DA神经元死亡。此外,从秀丽隐杆线虫到毒素处理的小鼠模型和PD患者iPSC衍生的DA神经元,TRPM2介导的脆弱DA神经元死亡途径是保守的。脆弱的SNc-DA神经元损失是PD的主要症状和原因,因此TRPM2介导的通路是一个很有前途的治疗PD的靶点。
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来源期刊
Progress in Neurobiology
Progress in Neurobiology 医学-神经科学
CiteScore
12.80
自引率
1.50%
发文量
107
审稿时长
33 days
期刊介绍: Progress in Neurobiology is an international journal that publishes groundbreaking original research, comprehensive review articles and opinion pieces written by leading researchers. The journal welcomes contributions from the broad field of neuroscience that apply neurophysiological, biochemical, pharmacological, molecular biological, anatomical, computational and behavioral analyses to problems of molecular, cellular, developmental, systems, and clinical neuroscience.
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