Table 1.
UPS components and substrates in neuropathological diseases
| Disorder | Gene product and function |
|---|---|
| Parkinson disease | |
| Autosomal dominant (early onset) | α-Synuclein (SNCA) (PARK1), aggregates in Lewy bodies |
| Autosomal dominant (late onset) | Leucine-rich repeat kinase 2 (LRRK2) (PARK8), a CHIP ubiquitin ligase substrate, contains a Roc domain as found in SCF ligases |
| Autosomal dominant (late onset) | Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) (PARK5), a DUB, acts as an E3 ligase when dimerized, polymorphisms linked to rare forms of familial disease |
| Autosomal recessive (juvenile onset) | Parkin (PARK2), a subunit of a SCF E3 ubiquitin ligase |
| Autosomal recessive (early onset) | PINK1 (PARK6), promotes parkin ubiquitin ligase activity |
| Autosomal recessive (early onset) | DJ-1 (PARK7) chaperone, promotes parkin ubiquitin ligase activity |
| Spinocerebellar ataxias | |
| SCA1 | Ataxin-1, a UBE3A E3 ligase, mutation blocks its ubiquitination and association with the ubiquitin receptor A1Up and the DUB enzyme USP7 |
| SCA2 | Ataxin-2, associates with c-Cbl E3 ligase and is involved in membrane protein endocytosis, and is a parkin E3 ligase substrate |
| SCA3 | Ataxin-3, a deubiquitinating enzyme (DUB) |
| Prion diseases | Prions may block normal function of the proteasome, HECT2D E3 ubiquitin ligase haplotypes are associated with vCJD and Kuru |
| Autosomal recessive ALS | ALS2, an endosomal membrane associated protein involved in endosome membrane fusion and trafficking, mutation decreases ALS2 protein stability |
| Angelman syndrome | Loss or mutation of UBE3A E3 ligase at Angelman/Prader–Willi locus |
| Rett syndrome | Decreased UBE3A E3 ligase due to MECP2 mutations |
| Autism | Copy number alterations of UBE3A and other UPS genes |
| Giant axon neuropathy | Mutation of gigaxonin, an E3 ubiquitin ligase |
| IBMPFD | Mutation of valosin-containing protein (VCP), involved in ubiquitin-mediated processing of membrane and cytosolic proteins. |
| Sporadic IBM | VCP and ubiquitin are found in inclusion bodies. |
| von Hippel–Lindau disease | pVHL, substrate-binding subunit of ubiquitin ligase targeting HIF1-α |
| Medulloblastoma | Overexpression of several signaling pathway genes that are ubiquitinated by the SCF: c-myc, β-catenin, Gli, stabilizing mutations of Gli and β-catenin prevent their ubiquitin-dependent proteolysis |
| Adamantinomatous craniopharyngioma | Stabilizing β-catenin mutations preventing its ubiquitin-dependent proteolysis |
| Gliomas | Misregulation and mutation of cell cycle control proteins regulated by the UPS: CDKs, CDK inhibitors, p53, altered expression of APC/C E3 ubiquitin ligase regulators Emi1 and RASSF1A |