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Crif1 deficiency in dopamine neurons triggers early-onset parkinsonism

Molecular Psychiatry volume 28, pages 4474–4484 (2023)Cite this article

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Abstract

Mitochondrial dysfunction has been implicated in Parkinson’s Disease (PD) progression; however, the mitochondrial factors underlying the development of PD symptoms remain unclear. One candidate is CR6-interacting factor1 (CRIF1), which controls translation and membrane insertion of 13 mitochondrial proteins involved in oxidative phosphorylation. Here, we found that CRIF1 mRNA and protein expression were significantly reduced in postmortem brains of elderly PD patients compared to normal controls. To evaluate the effect of Crif1 deficiency, we produced mice lacking the Crif1 gene in dopaminergic neurons (DAT-CRIF1-KO mice). From 5 weeks of age, DAT-CRIF1-KO mice began to show decreased dopamine production with progressive neuronal degeneration in the nigral area. At ~10 weeks of age, they developed PD-like behavioral deficits, including gait abnormalities, rigidity, and resting tremor. L-DOPA, a medication used to treat PD, ameliorated these defects at an early stage, although it was ineffective in older mice. Taken together, the observation that CRIF1 expression is reduced in human PD brains and deletion of CRIF1 in dopaminergic neurons leads to early-onset PD with stepwise PD progression support the conclusion that CRIF1-mediated mitochondrial function is important for the survival of dopaminergic neurons.

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Fig. 1: Decreased expression of CRIF1 in the SNpc of PD patients.
Fig. 2: Progressive decrease in TH expression in DAT-CRIF1-KO mice created using the Cre-loxP system.
Fig. 3: Progressive decrease in dopamine and its metabolites in the nigrostriatal pathway with mitochondrial dysfunction in DAT-CRIF1-KO mice.
Fig. 4: Increased GFAP and Iba-1 expression in the nigrostriatal pathway of DAT-CRIF1-KO mice.
Fig. 5: Decreased behavioral activity in DAT-CRIF1-KO mice and recovery with L-DOPA.

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIP) (2017R1A5A2015385, 2022R1A2C2002756 to JYH; 2022R1A2C3013280, RS-2023-00266872 to DK; 2020M3E5D9079742, 2022R1A2C3013138 to HR); a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &Welfare, Republic of Korea (HR22C1734 to JYH); Hong Kong Research Grants Council Theme-based Research Scheme (T13-607/12R) grant to SKC; an NIH Grant (R01NS109537 to JL) and a KIST Grant (2E32233 to HR).

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Author notes

  1. These authors contributed equally: Jun Young Heo, Ah Hyung Park, Min Joung Lee.

Authors and Affiliations

  1. Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea

    Jun Young Heo, Min Joung Lee, Min Jeong Ryu, Yun Seon Jang, Soo Jeong Kim, So Yeon Shin & Gi Ryang Kweon

  2. Department of Medical Science, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea

    Jun Young Heo & Min Joung Lee

  3. Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea

    Jun Young Heo & Min Joung Lee

  4. Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea

    Ah Hyung Park & Daesoo Kim

  5. Research Center for Endocrine and Metabolic Diseases, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea

    Yong Kyung Kim

  6. Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea

    Hyo Jin Son & Onyou Hwang

  7. Boston University Alzheimer’s Disease Research Center and Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA

    Thor D. Stein & Junghee Lee

  8. VA Bedford Healthcare System, Bedford, MA, 01730, USA

    Thor D. Stein

  9. VA Boston Healthcare System, Boston, MA, 02130, USA

    Thor D. Stein

  10. Electron Microscopy Research center, Korea Basic Science Institute, Cheongju, 28119, Republic of Korea

    Yang Hoon Huh

  11. Faculty of Medicine & Dr Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau SAR, China

    Sookja K. Chung

  12. State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China

    Sookja K. Chung

  13. Department of Pathology, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea

    Song Yi Choi & Jin Man Kim

  14. Graduate School of Medical Science and Education, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea

    Minho Shong

  15. Brain Science Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea

    Seung Jae Hyeon & Hoon Ryu

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Contributions

JYH, AHP, HR, GRK and DK designed the research; JYH, AHP, MJL, YHH, YKK, YSJ, SKC, MJR, SYC, SJH and SJK performed experiments; JL collected human tissue; SYS, HJS and TDS contributed to the preparation of research tools and sampling; JMK, OH, SKC, MJR and MS analyzed data; JYH, AHP, MJL, HR, GRK, SKC and DK wrote the paper.

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Correspondence to Hoon Ryu, Daesoo Kim or Gi Ryang Kweon.

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Heo, J.Y., Park, A.H., Lee, M.J. et al. Crif1 deficiency in dopamine neurons triggers early-onset parkinsonism. Mol Psychiatry 28, 4474–4484 (2023). https://doi.org/10.1038/s41380-023-02234-5

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