Atypical Ubiquitination and Parkinson’s Disease

Abstract

Ubiquitination (the covalent attachment of ubiquitin molecules to target proteins) is one of the main post-translational modifications of proteins. Historically, the type of polyubiquitination, which involves K48 lysine residues of the monomeric ubiquitin, was the first studied type of ubiquitination. It usually targets proteins for their subsequent proteasomal degradation. All the other types of ubiquitination, including monoubiquitination; multi-monoubiquitination; and polyubiquitination involving lysine residues K6, K11, K27, K29, K33, and K63 and N-terminal methionine, were defined as atypical ubiquitination (AU). Good evidence now exists that AUs, participating in the regulation of various cellular processes, are crucial for the development of Parkinson’s disease (PD). These AUs target various proteins involved in PD pathogenesis. The K6-, K27-, K29-, and K33-linked polyubiquitination of alpha-synuclein, the main component of Lewy bodies, and DJ-1 (another PD-associated protein) is involved in the formation of insoluble aggregates. Multifunctional protein kinase LRRK2 essential for PD is subjected to K63- and K27-linked ubiquitination. Mitophagy mediated by the ubiquitin ligase parkin is accompanied by K63-linked autoubiquitination of parkin itself and monoubiquitination and polyubiquitination of mitochondrial proteins with the formation of both classical K48-linked ubiquitin chains and atypical K6-, K11-, K27-, and K63-linked polyubiquitin chains. The ubiquitin-specific proteases USP30, USP33, USP8, and USP15, removing predominantly K6-, K11-, and K63-linked ubiquitin conjugates, antagonize parkin-mediated mitophagy.

Proteasome Interactome and Its Role in the Mechanisms of Brain Plasticity

“…Since the development of neurodegenerative pathology is frequently associated with regioselective decrease in the functional activity of proteasomes, a positive therapeutic effect could be obviously provided by the factors that increase activity of proteasomes. The possibility of pharmacological inhibition of deubiquitinase activity is currently considered as one of the main approaches [109]. Blockade of these enzymes facilitates entry of the ubiquitinated substrates into proteasomes for subsequent proteolytic degradation.…”

“…This leads to the changes in the presynaptic zones and contributed to the development of defects in protein homeostasis on the periphery of neurons. In addition, PI31 tightly binds to the Ntc/FBXO7/PARK15 F-box protein [107,108]; mutations in this protein are accompanied by proteasome dysfunction and cause development of the juvenile form of Parkinson's disease [109]. Binding of another adapter protein, Ecm29, to myosins and kinesins, facilitates interaction of proteasomes with various cell compartments [110].…”

USP48 alleviates bone cancer pain and regulates MrgC stabilization in spinal cord neurons of male mice

“…Mitochondrial USP30 shows a preference for chains with a K6/K48 branch over homotypic spliceosomes (Deol et al, 2020). Multiple deubiquitylases remove K6‐, K11‐ and K63‐linked polymers to antagonize Parkin‐mediated mitophagy (Buneeva & Medvedev, 2022). The deubiquitylase TRABID recognizes and cleaves the K29/K48 branched chain to protect the E3 ligase HECTD1 from self‐ubiquitination and degradation (Harris et al, 2021).…”

Koumine inhibits RANKL‐induced ubiquitination and NF‐κB activation to prevent ovariectomy and aging‐induced bone loss

“…Ubiquitination, a versatile posttranslational modification, performs various roles within cells, it operates through the collaborative action of E1/2/3 enzymes to bind ubiquitin to substrate proteins 20 . Various polyubiquitin chains can be formed by ubiquitin, among which K48/K63‐linked polyubiquitin chains are the most common 21–24 . K48 chains mainly mediate protein proteasomal degradation, 25,26 while K63 chain‐linked polyubiquitination modifications are associated with other cellular processes, including endocytosis, DNA damage response, and immune responses 27,28 …”

“…20 Various polyubiquitin chains can be formed by ubiquitin, among which K48/K63-linked polyubiquitin chains are the most common. [21][22][23][24] K48 chains mainly mediate protein proteasomal degradation, 25,26 while K63 chain-linked polyubiquitination modifications are associated with other cellular processes, including endocytosis, DNA damage response, and immune responses. 27,28 The dimeric transcription factor NF-κB consists of members from the Rel family, including Rel-A, Rel-B, c-Rel, p50, and p52.…”