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Review
. 2024 Jan 21;25(2):1303.
doi: 10.3390/ijms25021303.

Ubiquitin Carboxyl-Terminal Hydrolase L1 and Its Role in Parkinson's Disease

Olga Buneeva  1 , Alexei Medvedev  1
Affiliations
Review

Ubiquitin Carboxyl-Terminal Hydrolase L1 and Its Role in Parkinson's Disease

Olga Buneeva et al. Int J Mol Sci. .

Abstract

Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), also known as Parkinson's disease protein 5, is a highly expressed protein in the brain. It plays an important role in the ubiquitin-proteasome system (UPS), where it acts as a deubiquitinase (DUB) enzyme. Being the smallest member of the UCH family of DUBs, it catalyzes the reaction of ubiquitin precursor processing and the cleavage of ubiquitinated protein remnants, thus maintaining the level of ubiquitin monomers in the brain cells. UCHL1 mutants, containing amino acid substitutions, influence catalytic activity and its aggregability. Some of them protect cells and transgenic mice in toxin-induced Parkinson's disease (PD) models. Studies of putative protein partners of UCHL1 revealed about sixty individual proteins located in all major compartments of the cell: nucleus, cytoplasm, endoplasmic reticulum, plasma membrane, mitochondria, and peroxisomes. These include proteins related to the development of PD, such as alpha-synuclein, amyloid-beta precursor protein, ubiquitin-protein ligase parkin, and heat shock proteins. In the context of the catalytic paradigm, the importance of these interactions is not clear. However, there is increasing understanding that UCHL1 exhibits various effects in a catalytically independent manner through protein-protein interactions. Since this protein represents up to 5% of the soluble protein in the brain, PD-related changes in its structure will have profound effects on the proteomes/interactomes in which it is involved. Growing evidence is accumulating that the role of UCHL1 in PD is obviously determined by a balance of canonic catalytic activity and numerous activity-independent protein-protein interactions, which still need better characterization.

Keywords: Parkinson’s disease; experimental models; pathogenic mutations; ubiquitin carboxyl-terminal hydrolase L1; ubiquitin–proteasome system.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
A simplified scheme illustrating the ubiquitination/deubiquitination process. The ubiquitination process includes several sequential stages that involve several enzymes: ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3). Their concerted action results in the covalent attachment of the ubiquitin moiety to target protein substrates (S) for proteasomal degradation. Deubiquitinases (DUBs) catalyze the cleavage of ubiquitin molecules from target proteins (and ubiquitinated protein remnants) and thus maintain (mono)ubiquitin levels in the cell for subsequent reuse. An asterisk at E3 shows the involvement of different ligases in the interaction with E2: RING E3 ligases (E3*) catalyze the transfer of ubiquitin directly from E2 to the substrate, while in the case of HECT or RBR E3 ligases (E3), the activated ubiquitin is first transferred from E2 to E3 and then transferred to the substrate from the E3 ligases. Ubiquitin molecules are shown as green circles (modified from [11]).
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