Table 1 Ubiquitin-signalling genes associated with neurodegenerative disease.
From: Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities
Gene | Mutation, expression | Disease | Function/pathology | Ref | |
|---|---|---|---|---|---|
Ubiquitin Ligases | CHIP | Upregulated | AD | Several potential roles in AD, including the ubiquitination of phosphorylated tau. | [211] |
HACE1 | Downregulated in striatum | HD | Implicated in the Nrf2-mediated antioxidative stress response. | [212] | |
HRD1 | Downregulated in cerebral cortex | AD | Regulates ER-associated degradation and is potentially involved in APP turnover. | [213] | |
Nedd4 | Upregulated | AD, HD, PD, ALS | Nedd4 family mediates endocytosis and lysosomal degradation of cell surface receptors (such as DAT, IGF-1R and AMPAR), regulates transmitter homoeostasis and synaptic plasticity. | ||
PRKN (PARK2) | LOF mutation | PD | Parkin ubiquitinates outer mitochondrial membrane proteins to drive mitophagy. Also implicated in EGFR endocytic trafficking and inflammation. | [23] | |
RNF182 | Upregulated | AD | Regulates the turnover of an essential component of the neurotransmitter release machinery. | [214] | |
TRAF6 | Upregulated in substantia nigra | PD | Ubiquitinates α-synuclein and co-localises with Lewy bodies. | ||
TTC3 | Mutation, downregulated | AD | Regulates neuronal differentiation and Akt signalling. | ||
DUBs | UCHL1 | Downregulated | AD, PD | Implicated in the degradation of disease-associated aggregates. | |
LOF mutation | PD | ||||
USP9X | Downregulated in substantia nigra | PD | Regulates α-synuclein ubiquitination and is present in Lewy bodies, regulates turnover of pro-survival MCL1. | [133] | |
USP9Y | Downregulated (in males) | AD | Based on high sequence similarity with USP9X, may also regulate α-synuclein and phospho-tau. | [131] | |
Autophagy receptors | OPTN | LOF mutation | ALS | Major role in autophagy, including the removal of damaged mitochondria (mitophagy). Also implicated in other cell functions, such as innate immune response. | |
p62/SQSTM1 | LOF mutation | ALS | Important for autophagy and aggrephagy and can be detected in intraneuronal inclusion bodies. | ||
Other ubiquitin signalling genes | USP13 | Upregulated | AD, PD | Implicated in tau and α-synuclein clearance, as well as in Parkin ubiquitination. | |
FBXO7 | LOF mutation | PD | A component of the SCF E3 ligase complex that is involved in PINK1/Parkin mitophagy. | [221] | |
LRSAM1 | LOF mutation | PD | Involved in receptor endocytosis and ubiquitinating intracellular bacteria for autophagic clearance. | ||
PINK1 | LOF mutation | PD | A Ser/Thr kinase responsible for ubiquitin and Parkin phosphorylation during mitophagy. | ||
TBK1 | LOF mutation | ALS | A multifunctional Ser/Thr kinase, phosphorylates IRF3 during innate immunity and phosphorylates autophagy receptors to enhancing binding to ubiquitin and LC3. | [224] | |
UBB | Mutation | AD | Polyubiquitin precursor protein and a transcriptional +1 frameshift mutation that causes proteasome impairment and mitochondrial dysfunction. | [3] | |
UBQLN1 | Splice variants | AD | Promotes Lys63 polyubiquitination of APP to limit its trafficking and Aβ secretion | ||
UBQLN2 | LOF mutation | ALS, FTD | Shuttles ubiquitinated proteins, including protein aggregates, to the proteasome for degradation. | ||
VCP | LOF mutation | ALS | An AAA-ATPase that extracts ubiquitinated proteins from membranes/structures, often for proteasomal degradation. | [225] |
