Table 2 Immunotherapies targeting DJ-1-related neuroinflammatory pathways in Parkinson’s disease
From: PARK7/DJ-1 in microglia: implications in Parkinson’s disease and relevance as a therapeutic target
Compound | Target | Phase | Mechanism of action and model | References |
|---|---|---|---|---|
Therapeutical inhibition of NLRP3 inflammasome, cGAS/STING and NFkB in Parkinson’s disease | ||||
MCC950 | NLRP3 inflammasome inhibitor | Pre-clinical | Oral administration of MCC950 to 6-OHDA mouse model of PD and pre-formed fibril (PFF) mouse model of PD showed improved motor functions and prevented loss of dopamine and its metabolites | [122] |
Nilotinib (Tasigna®, AMN107) | Inhibits microglia-mediated neuroinflammation via NFκB Tyrosine kinase inhibitor | Proof of concept in vitro and in vivo | LPS induced neurodegeneration in BV-2 cells and mouse | [199] |
Inhibits microglia-mediated neuroinflammation via NFκB Tyrosine kinase inhibitor | Clinical trial Phase II double+-blind placebo-controlled study | Long term safety in PD patients after subcutaneous injection of 150 mg/kg and 300 mg/kg nilotinib | [200] | |
NPT520-34 | Reduces α-syn accumulation and upregulation of microtubule-associated protein 1A/1B light chain 3, a central protein in the autophagy pathway (referred to as LC3) | Pre-clinical Phase I clinical trial NCT03954600 | Anti-inflammatory effects in wildtype LPS-challenged mice. Decrease α-syn load in brain and increase LC3 protein abundance and improve motor symptoms in mouse line 61 | [201] NCT03954600 |
Dimethyl fumarate | NRF2 enhancer Decreased microgliosis and astrogliosis | Proof of concept in mouse model | NRF2 KO mice Pretreatment with dimethyl fumarate prevented neurodegeneration in 6-OHDA mouse model | [202] [203] |
DJ-1 enhancers and stabilizers | ||||
UCP0045037/compound A | DJ-1 enhancer. Binding C106 | Pre-clinical Proof of concept | DJ-1 protected against neuronal degeneration in the rotenone model 6-OHDA model Better behavioral outcomes, less neuronal loss in SN | [169] [171] |
UCP0054278/compound B | UCP0054278 treatment protected against neuronal death in a concentration-dependent manner in both 6-OHDA and rotenone model | [170] | ||
Compound-23 | Binding of DJ-1 and promoting neuroprotective effects of DJ-1 by preventing excessive oxidation of DJ-1 and keeping it in its active form Found via zinc compound library screening | Pre-clinical Proof of concept | Protective against PD (Rotenone and 6-OHDA) and middle cerebral artery occlusion (MCAO), stroke model Had better neuroprotective effects than compound B MPTP model. Rescued rotarod retention and neuronal loss in SN | [204] [205] |
ND-13 A DJ-1 peptide | ND-13 A DJ-1 peptide | Pre-clinical Proof of concept | By preventing the oxidation of DJ-1 and maintaining the reduced DJ-1 it inhibits oxidative stress-induced toxicity Can cross the BBB and also works after subcutaneous injection | [206] |
Phenyl butyrate | Neuroprotective Upregulates DJ-1 | Pilot study in animals | Improving outcomes in the MPTP mouse model of PD | [175] |
Withaferin A | Upregulates DJ-1 and NRF2 via STING Data extracted from patient data | Proof of concept in a small group of animals | Withaferin A treatment in MPTP-treated mice upregulated DJ-1 and NRF2 and suppressed STING, thereby protecting against DA neuronal loss | [166] |