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Deubiquitinating enzymes (DUBs): decipher underlying basis of neurodegenerative diseases

Molecular Psychiatry volume 27, pages 259–268 (2022)Cite this article

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Abstract

Neurodegenerative diseases (NDs) are characterized by the aggregation of neurotoxic proteins in the central nervous system. Aberrant protein accumulation in NDs is largely caused by the dysfunction of the two principal protein catabolism pathways, the ubiquitin-proteasome system (UPS), and the autophagy–lysosomal pathway (ALP). The two protein quality control pathways are bridged by ubiquitination, a post-translational modification that can induce protein degradation via both the UPS and the ALP. Perturbed ubiquitination leads to the formation of toxic aggregates and inclusion bodies that are deleterious to neurons. Ubiquitination is promoted by a cascade of ubiquitinating enzymes and counter-regulated by deubiquitinating enzymes (DUBs). As fine-tuning regulators of ubiquitination and protein degradation, DUBs modulate the stability of ND-associated pathogenic proteins including amyloid β protein, Tau, and α-synuclein. Besides, DUBs also influence ND-associated mitophagy, protein secretion, and neuroinflammation. Given the various and critical functions of DUBs in NDs, DUBs may become potential therapeutic targets for NDs.

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Fig. 1: Role of DUBs in AD.
Fig. 2: Role of DUBs in PD.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (81971143 and 81900496), the Qianjiang Talent Program of Zhejiang Province (QJD1902017), and the German Research Foundation (DFG-SFB854-A30N) to XW, and grants from the German Research Foundation (DFG-SFB854-A05 and DFG under Germany’s Excellence Strategy—EXC 2155 “RESIST”—Project ID 390874280) to DS.

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  1. These authors contributed equally: Baohua Liu, Jing Ruan.

Authors and Affiliations

  1. Department of Neurological Rehabilitation, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China

    Baohua Liu, Meng Chen & Xu Wang

  2. Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

    Jing Ruan

  3. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China

    Zhongding Li, Gloria Manjengwa & Xu Wang

  4. Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany

    Dirk Schlüter & Xu Wang

  5. Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany

    Dirk Schlüter

  6. Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, School of Mental Health and Kangning Hospital, The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, China

    Weihong Song

  7. Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, China

    Weihong Song

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Liu, B., Ruan, J., Chen, M. et al. Deubiquitinating enzymes (DUBs): decipher underlying basis of neurodegenerative diseases. Mol Psychiatry 27, 259–268 (2022). https://doi.org/10.1038/s41380-021-01233-8

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