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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Precise control of mitophagy through ubiquitin proteasome system and deubiquitin proteases and their dysfunction in Parkinson's disease

  • Park, Ga Hyun (Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University) ;
  • Park, Joon Hyung (Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University) ;
  • Chung, Kwang Chul (Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University)
  • Received : 2021.07.05
  • Accepted : 2021.10.06
  • Published : 2021.12.31
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Abstract

Parkinson's disease (PD) is one of the most common neurodegenerative diseases in the elderly population and is caused by the loss of dopaminergic neurons. PD has been predominantly attributed to mitochondrial dysfunction. The structural alteration of α-synuclein triggers toxic oligomer formation in the neurons, which greatly contributes to PD. In this article, we discuss the role of several familial PD-related proteins, such as α-synuclein, DJ-1, LRRK2, PINK1, and parkin in mitophagy, which entails a selective degradation of mitochondria via autophagy. Defective changes in mitochondrial dynamics and their biochemical and functional interaction induce the formation of toxic α-synuclein-containing protein aggregates in PD. In addition, these gene products play an essential role in ubiquitin proteasome system (UPS)-mediated proteolysis as well as mitophagy. Interestingly, a few deubiquitinating enzymes (DUBs) additionally modulate these two pathways negatively or positively. Based on these findings, we summarize the close relationship between several DUBs and the precise modulation of mitophagy. For example, the USP8, USP10, and USP15, among many DUBs are reported to specifically regulate the K48- or K63-linked de-ubiquitination reactions of several target proteins associated with the mitophagic process, in turn upregulating the mitophagy and protecting neuronal cells from α-synuclein-derived toxicity. In contrast, USP30 inhibits mitophagy by opposing parkin-mediated ubiquitination of target proteins. Furthermore, the association between these changes and PD pathogenesis will be discussed. Taken together, although the functional roles of several PD-related genes have yet to be fully understood, they are substantially associated with mitochondrial quality control as well as UPS. Therefore, a better understanding of their relationship provides valuable therapeutic clues for appropriate management strategies.

Keywords

Acknowledgement

This work was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korea government (MSIT, No. 2021R1A2C1005469 to KCC). We apologize to several researchers whose work could not be cited in this review due to space limitations.

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