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

Acta Pharmacologica Sinica volume 44, pages 1948–1961 (2023)Cite this article

Abstract

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.

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Fig. 1: DJ-1 deficiency affects DA metabolic gene expression according to RNAseq.
Fig. 2: MAO-B but not MAO-A expression is upregulated by DJ-1 deficiency.
Fig. 3: The regulation of MAO-B expression by DJ-1 is EGR1 dependent.
Fig. 4: EGR1 expression is activated by DJ-1 deficiency.
Fig. 5: AP-1 is responsible for DJ-1 deficiency-induced EGR1 and MAO-B expression.
Fig. 6: DJ-1 interacts with RACK1.
Fig. 7: PKC activation contributes to MAO-B expression by DJ-1 deficiency.
Fig. 8: Inhibition of MAO-B activity prevents the sensitization to neuronal damage caused by DJ-1 deficiency.
Fig. 9: Schematic diagram of the mechanism by which DJ-1 regulates MAO-B expression.

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Data availability

The data supporting the findings in this study are available within the paper. Other transcriptome sequencing and mass spectrometry data supporting the findings of this study are available from the corresponding author on reasonable request.

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Funding

This work was 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) and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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  1. These authors contributed equally: Le-le Liu, Yu Han, Zi-jia Zhang

Authors and Affiliations

  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

    Le-le Liu, Yu Han, Yi-qi Wang, Yu-wei Hu, Guang-hui Wang & Hai-gang Ren

  2. Qingdao Municipal Hospital of Shandong Province, Qingdao, 266011, China

    Zi-jia Zhang

  3. Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, 194064, Russia

    Elena Kaznacheyeva

  4. Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China

    Jian-qing Ding

  5. Laboratory of Clinical Pharmacy, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, 215153, China

    Dong-kai Guo

  6. Department of General Surgery, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, 215200, China

    Bin Li

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Contributions

HGR and BL designed the study. LLL, YH, and ZJZ performed most of the experiments. YQW, YWH, and BL performed some of the biochemical and cellular experiments. EK, JQD, and DKG analyzed the data. HGR drafted the paper. BL and GHW revised the paper. All authors read and approved the paper.

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Correspondence to Bin Li or Hai-gang Ren.

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Liu, Ll., Han, Y., Zhang, Zj. et al. Loss of DJ-1 function contributes to Parkinson’s disease pathogenesis in mice via RACK1-mediated PKC activation and MAO-B upregulation. Acta Pharmacol Sin 44, 1948–1961 (2023). https://doi.org/10.1038/s41401-023-01104-8

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