Cell senescence induced by toxic interaction betweenα-synuclein and iron precedes nigral dopaminergic neuron loss in a mouse model of Parkinson’s disease  

作　　者：Qing-qing Shen Xian-hui Jv Xi-zhen Ma Chong Li Lin Liu Wen-ting Jia Le Qu Lei-lei Chen Jun-xia Xie 

机构地区：[1]Institute of Brain Science and Disease,Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders,Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders,Qingdao University,Qingdao 266021,China

出　　处：《Acta Pharmacologica Sinica》2024年第2期268-281,共14页中国药理学报（英文版）

基　　金：supported by grants from National Natural Science Foundation of China(32170984);Natura Science Foundation of Shandong Province(ZR2020YQ23,ZR2023QH110);Qingdao Postdoctoral Research Project(QDBSH20220202204).

摘　　要：Cell senescence has been implicated in the pathology of Parkinson’s disease(PD).Both abnormalα-synuclein aggregation and iron deposition are suggested to be the triggers,facilitators,and aggravators during the development of PD.In this study,we investigated the involvement ofα-synuclein and iron in the process of cell senescence in a mouse model of PD.In order to overexpressα-syn-A53T in the substantia nigra pars compacta(SNpc),humanα-syn-A53T was microinjected into both sides of the SNpc in mice.We found that overexpression ofα-syn-A53T for one week induced significant pro-inflammatory senescence-associated secretory phenotype(SASP),increased cell senescence-related proteins(β-gal,p16,p21,H2A.X andγ-H2A.X),mitochondrial dysfunction accompanied by dysregulation of iron-related proteins(L-ferritin,H-ferritin,DMT1,IRP1 and IRP2)in the SNpc.In contrast,significant loss of nigral dopaminergic neurons and motor dysfunction were only observed after overexpression ofα-syn-A53T for 4 weeks.In PC12 cells stably overexpressingα-syn-A53T,iron overload(ferric ammonium citrate,FAC,100μM)not only increased the level of reactive oxygen species(ROS),p16 and p21,but also exacerbated the processes of oxidative stress and cell senescence signalling induced byα-syn-A53T overexpression.Interestingly,reducing the iron level with deferoxamine(DFO)or knockdown of transferrin receptor 1(TfR1)significantly improved both the phenotypes and dysregulated proteins of cell senescence induced byα-syn-A53T overexpression.All these evidence highlights the toxic interaction between iron andα-synuclein inducing cell senescence,which precedes nigral dopaminergic neuronal loss in PD.Further investigation on cell senescence may yield new therapeutic agents for the prevention or treatment of PD.

关 键 词：Parkinson’s disease cell senescence dopaminergic neurons Α-SYNUCLEIN IRON transferrin receptor 1 

分 类 号：R742.5[医药卫生—神经病学与精神病学]