Dataset Information

Deubiquitinating Enzymes in Parkinson's Disease.

ABSTRACT: Mitochondrial dysfunction and neurodegeneration have been directly correlated in many neurodegenerative disorders. Parkinson's disease (PD) in particular has been extensively studied in this context because of its well-characterized association with mitophagy, a selective type of autophagy that degrades mitochondria. Mitophagy is triggered by ubiquitin modification of proteins residing on the surface of mitochondria. Therefore, mitophagy is subject to suppression by deubiquitination. In recent years, many deubiquitinase enzymes (DUBs) emerged as therapeutic targets to compensate hindered mitophagy in PD. It is reasonable that inhibition of specific DUBs should induce mitophagy by blocking deubiquitination of mitochondrial proteins, although the signaling pathway is not always that linear. The broad aspect suggests that there could be cross talks among DUBs, which may in turn have synergistic effect to rescue the disease progression. In this short review we have highlighted DUBs that hold therapeutic value in the field of neurodegenerative diseases, PD in particular.

SUBMITTER: Chakraborty J

PROVIDER: S-EPMC7283616 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Deubiquitinating Enzymes in Parkinson's Disease.

Chakraborty Joy J Ziviani Elena E

Frontiers in physiology 20200603

Mitochondrial dysfunction and neurodegeneration have been directly correlated in many neurodegenerative disorders. Parkinson's disease (PD) in particular has been extensively studied in this context because of its well-characterized association with mitophagy, a selective type of autophagy that degrades mitochondria. Mitophagy is triggered by ubiquitin modification of proteins residing on the surface of mitochondria. Therefore, mitophagy is subject to suppression by deubiquitination. In recent y ...[more]

PMID: 32581833

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Project description:The post-translational attachment of one or several ubiquitin molecules to a protein generates a variety of targeting signals that are used in many different ways in the cell. Ubiquitination can alter the activity, localization, protein-protein interactions or stability of the targeted protein. Further, a very large number of proteins are subject to regulation by ubiquitin-dependent processes, meaning that virtually all cellular functions are impacted by these pathways. Nearly a hundred enzymes from five different gene families (the deubiquitinating enzymes or DUBs), reverse this modification by hydrolyzing the (iso)peptide bond tethering ubiquitin to itself or the target protein. Four of these families are thiol proteases and one is a metalloprotease. DUBs of the Ubiquitin C-terminal Hydrolase (UCH) family act on small molecule adducts of ubiquitin, process the ubiquitin proprotein, and trim ubiquitin from the distal end of a polyubiquitin chain. Ubiquitin Specific Proteases (USPs) tend to recognize and encounter their substrates by interaction of the variable regions of their sequence with the substrate protein directly, or with scaffolds or substrate adapters in multiprotein complexes. Ovarian Tumor (OTU) domain DUBs show remarkable specificity for different Ub chain linkages and may have evolved to recognize substrates on the basis of those linkages. The Josephin family of DUBs may specialize in distinguishing between polyubiquitin chains of different lengths. Finally, the JAB1/MPN+/MOV34 (JAMM) domain metalloproteases cleave the isopeptide bond near the attachment point of polyubiquitin and substrate, as well as being highly specific for the K63 poly-Ub linkage. These DUBs regulate proteolysis by: directly interacting with and co-regulating E3 ligases; altering the level of substrate ubiquitination; hydrolyzing or remodeling ubiquitinated and poly-ubiquitinated substrates; acting in specific locations in the cell and altering the localization of the target protein; and acting on proteasome bound substrates to facilitate or inhibit proteolysis. Thus, the scope and regulation of the ubiquitin pathway is very similar to that of phosphorylation, with the DUBs serving the same functions as the phosphatase. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.

Dataset Information

Deubiquitinating Enzymes in Parkinson's Disease.

Publications

Deubiquitinating Enzymes in Parkinson's Disease.

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