Linking Ubiquitin Research to Drug Discovery

Neurological and Musculoskeletal

A lack or loss of adequate control of ubiquitin and autophagy signalling cascades has been attributed to and linked with neurodegenerative diseases. Neurons rely heavily on the proper operation of these systems to function normally, such that perturbations in function in vulnerable neurons may result in protein aggregation, increased ER stress, and cell death. The regulation of muscle turnover has also been linked to control by the ubiquitin system.

This is not intended to be an exhaustive list of targets and disease associations but one that highlights some of the most recent work in a variety of therapeutic areas. There are other targets across the ubiquitin system that may be added to this list as well as further therapeutic applications of those already referenced – why not let us know of key ubiquitin system therapeutic associations that you have seen or are working on and help us build this resource. Submit your suggestions here.

Click here for reference list

Ubiquitin system targets expressed in the tissues of the CNS, PNS and musculature 71

 

Brain
DUBs: Ataxin-3L, Cezanne2, MYSM1, OTUB1, TRABID, UCHL1, USP3, USP6, USP9x, USP11, USP14, USP21, USP22, USP26, USP29, USP32, USP33, USP42, USP46, USP51, USP54
E3 ligases: Cul1/Rbx1Cul1/Rbx1/Skp1, Cul3/Rbx1, Cul5/Rnf7, DCNL1, CHIPIDOL, ITCH, RNF8, RNF11, ZNRF2 8

Spinal Cord
DUB: AMSH

Skeletal Muscle
DUBs: CSN5, EIF3F, OTUB2, OTUD1, USP2, USP13, USP19, USP38, USP39, USP49, USP54
E3 Ligases: IDOLITCH, CHIPCul5/Rnf7, MURF1

Ubiquitin system targets in neural and muscular disease 71

↓ – down regulated, ↑ – over-expressed, [ ] – mutated

 

Depression
DUB: USP46

Parkinson’s Disease
DUBs: UCHL1, USP25, USP40, Ataxin-3 53
E2 Conjugating enzymes: Ube2A 81
E3 Ligases: RNF11 21Parkin 27

Alzheimer’s Disease
DUBs: USP14 38
E1 Activating enzyme: APP-BP1/UBA3 73
E3 Ligases: Cul1/Rbx1 15CHIP 3, 5, Parkin 26

Neurodegenerative disease
DUBs: Ataxin-3UCHL1 46
E2 Conjugating enzymes: Ube2A 81, Ube2H 83, Ube2K 85
E3 Ligases: RNF11 22, DCNL1 24, CHIP 4

Brain related cancers
DUBs: ↓ Cezanne2, ↓ UCHL1, ↑ USP1, ↑ USP3, [USP532, ↓ USP11, [USP1539
E3 Ligases: CHIP 7

Musculoskeletal disorders and atrophy
E1 Activating enzyme: [Ube1] 72
E2 Conjugating enzyme: Ube2H 83
E3 Ligases:↑ MuRF1 90
DUBs: Ataxin-3Ataxin-3L, USP14 40, USP19 40
UBPs: [Optineurin] 80

↓ – down regulated, ↑ – over-expressed, [ ] – mutated

Click here for reference list