Table 2.

Atypical ubiquitination of proteins in PD and PD-related models.

Target Protein	Type of Ubiquitination	Enzymes Studied (E2, E3, DUBs, etc.)	Biological Effect	References
Histones H2B, H2A	Monoubiquitination	Not studied	Deubiquitination of histones H2A and H2B correlated with the accumulation of ubiquitin conjugates on the inclusion bodies and DNA damage. In contrast to control, brain mitochondria of MPTP-treated mice did not contain ubiquitinated histone H2A.	[62,79]
Alpha-synuclein	Multiple monoubiquitination	E3 ligase SIAH deubiquitinase USP9X	Alpha-synuclein monoubiquitination promoted aggregate formation in vitro and in vivo. Site-specific monoubiquitination provided different levels of alpha-synuclein degradation. USP9X regulated alpha-synuclein degradation.	[43,44,45,46,48,49]
Alpha-synuclein, proapoptotic PD-related protein RTP801	K63-linked polyubiquitination	HECT E3 ligase NEDD4	Nedd4 catalyzed K63-linked ubiquitination of alpha-synuclein in cells. K63-linked ubiquitin conjugates were detected in alpha-synuclein-positive inclusions in postmortem brains of PD patients. In cells (over)expressing Nedd4, alpha-synuclein content decreased. In the cell model of PD, 6-OHDA decreased NEDD4 and increased RTP801.	[86,87,88,89,90]
Alpha-synuclein and synphilin-1	K63-linked polyubiquitination	E3 ligase parkin, E2 enzyme UbcH13/Uev1a	K63-linked ubiquitination of alpha-synuclein and synphilin-1 promoted Lewy body formation.	[83,84,85]
Alpha-synuclein, DJ-1	K6-, K27-, and K29-linked polyubiquitination	E3 TRAF6	TRAF6 interaction with mutant DJ-1 and alpha-synuclein promoted the formation of atypical ubiquitin chains and insoluble DJ-1 aggregates.	[82,116]
DJ-1	Monoubiquitination, K63-linked polyubiquitination	E3 ligase parkin, PINK1, E3 ubiquitin ligase VHL	K63-linked polyubiquitination targets L166P mutant DJ-1 for the pathways other than proteasomal degradation. Parkin overexpression had no impact on the steady-state level of both L166P mutant and wild-type DJ-1.	[110]
LRRK2	K63-, K27-, and K29-linked polyubiquitination	E3 ubiquitin ligase CHIP (K63-) E3 ubiquitin ligase WSB1 (K27-, K29-)	LRRK2 is a substrate for CHIP, which regulates the steady-state level of LRRK2 via UPS degradation. WSB1 ubiquitinates LRRK2 through K27- and K29- linkage chains followed by LRRK2 aggregation and neuronal protection in primary neurons.	[124,125,126]
E3 ligase parkin. Outer mitochondrial membrane (OMM) proteins	Monoubiquitination. K6-, K11-, K27-, and K63-linked polyubiquitination and deubiquitination	PINK1; E3 ligase parkin; UBE2N; UBE2L3; UBE2D2; DUBs USP8, USP15, USP30, USP33, USP35, UCH-L1	In response to OMM depolarization, parkin (phosphorylated by PINK1) was autoubiquitinated (K63) and ubiquitinated mitochondrial proteins with the predominance of K11, K63, and K6 chains (with subsequent mitophagy). Deubiquitination of mitochondrial proteins negatively regulated mitophagy.	[127,128,129,130,131,132,133,134,135,136]
Miro1 GTPase	Predominantly K27- and some K11- and K29-linked polyubiquitination	PINK1, parkin	Mitochondrial damage caused parkin phosphorylation by PINK1, followed by K27-linked ubiquitination of the outer membrane Miro1, and retarded proteasomal degradation of Miro1.	[137]
Mitochondrial proteins	K63-linked polyubiquitination	E3 ligase parkin, E2 Ubc13	Under moderate mitochondrial stress conditions, parkin provides mitochondrial connectivity causing mitochondrial fission by catalyzing (together with E2 Ubc13) its K63-linked ubiquitination.	[138]
Glycogen synthase kinase 3 beta (Gsk3beta)	K63-linked polyubiquitination	SCFFbxo7/PARK15 ubiquitin ligase	The ubiquitination of the enzyme Gsk3beta negatively regulated its activity but not its localization.	[139]
NEMO, components of the NF-κB signaling pathway, and MAP kinases	M1-linked ubiquitination, K63-linked polyubiquitination	E3 ligase LUBAC	Increase in LUBAC-mediated M1-linked (linear) ubiquitination of NEMO	[140,141,142,143,144]