Bach1 derepression is neuroprotective in a mouse model of Parkinson’s disease

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by the loss of nigrostriatal dopaminergic neurons. Mounting evidence suggests that Nrf2 is a promising target for neuroprotective interventions in PD. However, electrophilic chemical properties of the canonical Nrf2-based drugs cause irreversible alkylation of cysteine residues on cellular proteins resulting in side effects. Bach1 is a known transcriptional repressor of the Nrf2 pathway. We report that Bach1 levels are up-regulated in PD postmortem brains and preclinical models. Bach1 knockout (KO) mice were protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity and associated oxidative damage and neuroinflammation. Functional genomic analysis demonstrated that the neuroprotective effects in Bach1 KO mice was due to up-regulation of Bach1-targeted pathways that are associated with both Nrf2-dependent antioxidant response element (ARE) and Nrf2-independent non-ARE genes. Using a proprietary translational technology platform, a drug library screen identified a substituted benzimidazole as a Bach1 inhibitor that was validated as a nonelectrophile. Oral administration of the Bach1 inhibitor attenuated MPTP neurotoxicity in pre- and posttreatment paradigms. Bach1 inhibitor–induced neuroprotection was associated with the up-regulation of Bach1-targeted pathways in concurrence with the results from Bach1 KO mice. Our results suggest that genetic deletion as well as pharmacologic inhibition of Bach1 by a nonelectrophilic inhibitor is a promising therapeutic approach for PD.

The NRF2-Dependent Transcriptional Regulation of Antioxidant Defense Pathways: Relevance for Cell Type-Specific Vulnerability to Neurodegeneration and Therapeutic Intervention

“…It is thought that microgliosis occurs early in disease progression and is sustained over its course [229]. This observed increased in microglial occupation could also explain a recent report of increased BACH1 expression in the PD post-mortem midbrain [230]. As we show in Figure 2b, microglia are enriched with Bach1, a transcriptional repressor of ARE-containing genes [4], so they would be a likely contributor.…”

“…As we show in Figure 2 b, microglia are enriched with Bach1 , a transcriptional repressor of ARE-containing genes [ 4 ], so they would be a likely contributor. This study goes on to show that BACH1 KO animals are more resilient to MPTP treatments, that and BACH1 inhibitors in wild-type animals attenuate MPTP-mediated toxicity [ 230 ]. These data suggest that the knockdown of BACH1 could be a viable strategy for promoting the neuroprotection of DAergic neurons in the context of PD.…”

The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, promote nuclear exclusion of BACH1 impairing its activity

“…BACH1 has recently gained visibility as a potential therapeutic target against a variety of conditions ranging from Parkinson's disease [ 18 ], bone destructive diseases [ 24 ], non-alcoholic steatohepatitis [ 30 ], atherosclerosis [ 31 ], insulin resistance [ 28 ], coronary artery disease [ 51 ] and aging related conditions [ 25 ]. In addition, BACH1 is a promising therapeutic target against tumour metastasis in various tumour types [ 40 , 43 , [52] , [53] , [54] , [55] , [56] ].…”

“…Despite their therapeutic potential for a variety of conditions, including Huntington's and Parkinson's disease [ 18 , 19 ], spinal cord injury [ 20 , 21 ], ischemia/reperfusion injury [ 22 ], pulmonary fibrosis [ 23 ], and cancer [ [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] ], only a few BACH1 inhibitors/degraders have been identified so far. The most widely used BACH1 degrader is hemin, a heme derivative.…”

“…Based on the differential effect of BACH1 versus KEAP1 inhibitors, we expect drugs with dual activity, targeting both transcription factors, to have broader and stronger anti-inflammatory and antioxidant properties with potentially greater therapeutic value than drugs targeting either protein individually. In that regard, we have reported a chemical derivative of cannabidiol with dual activity and protective effects in a cellular model of Huntington's disease [ 19 ] and a recent work characterised a novel dual BACH1/KEAP1 inhibitor with protective effects in a Parkinson's model [ 18 ].…”