Loss of DJ-1 function contributes to Parkinson’s disease pathogenesis in mice via RACK1-mediated PKC activation and MAO-B upregulation  

作　　者：Le-le Liu Yu Han Zi-jia Zhang Yi-qi Wang Yu-wei Hu Elena Kaznacheyeva Jian-qing Ding Dong-kai Guo Guang-hui Wang Bin Li Hai-gang Ren 

机构地区：[1]Laboratory of Molecular Neuropathology,Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Disorders&Department of Pharmacology,College of Pharmaceutical Sciences,Soochow University,Suzhou,215123,China [2]Qingdao Municipal Hospital of Shandong Province,Qingdao,266011,China [3]Institute of Cytology,Russian Academy of Sciences,Saint-Petersburg,194064,Russia [4]Department of Neurology and Institute of Neurology,Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine,Shanghai,200025,China [5]Laboratory of Clinical Pharmacy,Suzhou Hospital,Affiliated Hospital of Medical School,Nanjing University,Suzhou,215153,China [6]Department of General Surgery,Suzhou Ninth Hospital Affiliated to Soochow University,Suzhou,215200,China

出　　处：《Acta Pharmacologica Sinica》2023年第10期1948-1961,共14页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.32170987,31970966 and 32261133525);the Russian Science Foundation(No.23-44-00054);the Natural Science Foundation of Jiangsu Province(BK20200213);a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

摘　　要：Parkinson’s disease (PD) is a common neurodegenerative motor disorder characterized by a dramatic reduction in pars compacta of substantia nigra dopaminergic neurons and striatal dopamine (DA) levels. Mutations or deletions in the PARK7/DJ-1 gene are associated with an early-onset familial form of PD. DJ-1 protein prevents neurodegeneration via its regulation of oxidative stress and mitochondrial function as well as its roles in transcription and signal transduction. In this study, we investigated how loss of DJ-1 function affected DA degradation, ROS generation and mitochondrial dysfunction in neuronal cells. We showed that loss of DJ-1 significantly increased the expression of monoamine oxidase (MAO)-B but not MAO-A in both neuronal cells and primary astrocytes. In DJ-1-knockout (KO) mice, MAO-B protein levels in the substantia nigra (SN) and striatal regions were significantly increased. We demonstrated that the induction of MAO-B expression by DJ-1 deficiency depended on early growth response 1 (EGR1) in N2a cells. By coimmunoprecipitation omics analysis, we found that DJ-1 interacted with receptor of activated protein C kinase 1 (RACK1), a scaffolding protein, and thus inhibited the activity of the PKC/JNK/AP-1/EGR1 cascade. The PKC inhibitor sotrastaurin or the JNK inhibitor SP600125 completely inhibited DJ-1 deficiency-induced EGR1 and MAO-B expression in N2a cells. Moreover, the MAO-B inhibitor rasagiline inhibited mitochondrial ROS generation and rescued neuronal cell death caused by DJ-1 deficiency, especially in response to MPTP stimulation in vitro and in vivo. These results suggest that DJ-1 exerts neuroprotective effects by inhibiting the expression of MAO-B distributed at the mitochondrial outer membrane, which mediates DA degradation, ROS generation and mitochondrial dysfunction. This study reveals a mechanistic link between DJ-1 and MAO-B expression and contributes to understanding the crosslinks among pathogenic factors, mitochondrial dysfunction and oxidative stress in PD pathogenesis.

关 键 词：Parkinson’s disease DJ-1 MAO-B EGR1 RACK1 PKC 

分 类 号：R589.2[医药卫生—内分泌]