Nrf2/Bach1 Signaling Pathway in Parkinson’s Disease: Comparison
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Parkinson’s disease (PD) is the second most common neurodegenerative movement disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although a complex interplay of multiple environmental and genetic factors has been implicated, the etiology of neuronal death in PD remains unresolved. Various mechanisms of neuronal degeneration in PD have been proposed, including oxidative stress, mitochondrial dysfunction, neuroinflammation, α-synuclein proteostasis, disruption of calcium homeostasis, and other cell death pathways. While many drugs individually targeting these pathways have shown promise in preclinical PD models, this promise has not yet translated into neuroprotective therapies in human PD. This has consequently spurred efforts to identify alternative targets with multipronged therapeutic approaches. A promising therapeutic target that could modulate multiple etiological pathways involves drug-induced activation of a coordinated genetic program regulated by the transcription factor, nuclear factor E2-related factor 2 (Nrf2). Nrf2 regulates the transcription of over 250 genes, creating a multifaceted network that integrates cellular activities by expressing cytoprotective genes, promoting the resolution of inflammation, restoring redox and protein homeostasis, stimulating energy metabolism, and facilitating repair. Researchers propose that the transcriptional repressor of BTB and CNC homology 1 (Bach1), which antagonizes Nrf2, could serve as a promising complementary target for the activation of both Nrf2-dependent and Nrf2-independent neuroprotective pathways. Here this entry present the knowledge on the Nrf2/Bach1 signaling pathway, its role in various cellular processes, and the benefits of simultaneously inhibiting Bach1 and stabilizing Nrf2 using non-electrophilic small molecules as a novel therapeutic approach for PD.

  • Parkinson’s disease
  • Nrf2
  • Bach1
  • antioxidants

1. Parkinson’s Disease, a Heterogeneous Neurodegenerative Movement Disorder

Parkinson’s disease (PD) is the most common movement disorder that affects nearly 10 million people worldwide. The PD-patient population mainly comprises a segment of the elderly population above sixty. Furthermore, PD is the second most common neurodegenerative disease globally, ranking behind Alzheimer’s disease in prevalence and adverse social/economic impact. The United States alone is estimated to have approximately 1.2 million PD patients by 2030, which will cost 52 billion U.S. dollars annually in direct and indirect costs related to treatment, social security payments, and lost income [1][2]. In 1817, James Parkinson provided the first description of clinical cases of PD in his seminal essay, “Essay on the shaking palsy”, and even more than two centuries later, PD remains a condition with uncertain etiopathogenesis. Clinically, PD consists of four cardinal motor symptoms—commonly known as parkinsonian symptoms—that include rigidity, resting tremor, bradykinesia (slowness in movement), and postural instability resulting in gait dysfunction (reviewed in [3]).
Additionally, non-motor manifestations of PD include gastrointestinal dysfunction, cognitive impairment, depression, anxiety, hyposomnia, sleep disorders, and autonomic dysfunction. Interestingly, these non-motor symptoms appear long before the onset of motor-related symptoms [4][5]. Although most PD cases’ etiological factors are unknown and are described as sporadic PD, approximately 10–15% of all PD cases consist of a monogenic form of PD with a well-defined single causative genetic mutation. Currently, at least 23 loci and 19 disease-causing genes for PD have been found [6]. Although sporadic PD has no definitive etiological factors, recent population-based studies have identified distinct genetic risk factors that interact with well-known environmental factors in PD [3].

2. Bach1: Structural Domains, Expression, and Transcription-Dependent and Independent Roles

Bach1 belongs to one of the 19 phylogenetically related families of the basic region leucine zipper containing transcription factors. It is evolutionarily and closely linked to the cap “n” collar (CNC)-related basic-region leucine zipper transcription factor family that includes p45 NF-E2, Nrf1/LCR-F1/TCF11, Nrf2/ECH, and Nrf3 [7]. The Bach family is a relative newcomer in the evolutionary tree of bZIP proteins. It is found only in higher eukaryotes except for Ciona intestinalis, implicating that Bach proteins play a role in maintaining the complex functions of life in the higher eukaryotes [7]. At the same time, Bach1 is unique from Nrf2 and other CNC-related proteins because it contains a combination of two vastly distinctive domains: (1) Broad complex, tram track, bric-a-brac/poxvirus, and zinc finger (BTB/POZ) and (2) CNC-related bZip leucine fingers [8][9]. The BTB/POZ domain acts as a protein-interaction motif facilitating self-association and heterodimeric interaction with non-BTB proteins [10]. BTB family proteins, which include BTB-zinc finger (ZF), Skp1, and Elongin C, regulate diverse physiological roles that include transcriptional repression [11], cytoskeletal regulation [12][13], tetramerization, and the gating of ion channels [14], and the facilitation of ubiquitination [15].
As mentioned above, Bach1 possesses BTB/POZ and CNC-related bZip leucine finger domains [9]. Furthermore, Bach1 has multiple other domains with distinct functional roles [9][16][17][18][19]. Based on the functional role, the structure of Bach1 is categorized into five domains: (1) The BTB/POZ zinc finger domain (amino acids 16–122) at the N-terminal, (2) the heme regulatory motif (HRM) composed of dipeptide cysteine-proline (CP 1–6) recurring at six positions, (3) a CNC-type bZIP domain extending from amino acids 562–624, (4) an intracellular hyaluronic acid binding protein (IHABP/HMMR) site residing in the region encompassing residues 636–685, and (5) a cytoplasmic localization signal (CLS) composed of residues spanning 685–725.

2.1. Bach1 Expression and Transcriptional Regulation

Human Bach1 is ubiquitously expressed in all mammalian tissues [9]. In mice, Bach1 is expressed at high levels in hematopoietic cells, bone marrow cells, the thymus, and the liver from embryonic day 13.5 onwards. It is also expressed in the brains of adult mice. One of the earliest events in hematopoietic cell development is the induction of Bach1 [20]. The human Bach1 gene is localized on chromosome 21q22.1 (HC21) [21] and consists of five exons. The Bach1 promoter consists of three regions: (1) An upstream negative regulatory region, (2) a minimal core promoter region, and (3) a stimulatory region that resides between the first two regions. The minimal core promoter region exhibits the two well-conserved GC boxes that bind to a commonly expressed trans-acting DNA binding factor, SP1 (specificity protein 1). The basal expression of Bach1 is under the control of SP1 [22]. The same study showed that Bach1 alone indirectly represses its transcription through an unknown mechanism. However, it is shown to be mediated by the ARE site in the Bach1 promoter region [22]. The Bach1 promoter has two ARE sequences, ARE1 and ARE2, at +1411 and +1270 downstream of the TSS (transcription start site). The Nrf2 activating compounds induce Bach1 expression via the ARE1 site located at +1411 in an Nrf2-dependent fashion [23][24]. In addition to transcriptional regulation, based on the different domains of Bach1 protein, it is evident that its subcellular localization and cellular function are affected by various stimuli.

2.2. Transcription-Dependent and -Independent Mechanisms of Bach1

As a transcription factor, Bach1, similar to other CNC-related proteins, heterodimerizes with small musculoaponeurotic fibrosarcoma (MAF) proteins to form a dimeric or oligomeric complex that binds to small Maf responsive element (MARE) consensus sites on the DNA. Once bound to the corresponding DNA-binding elements, small MAF-Bach1 heterodimers act as a transcriptional repressor by recruiting methionine adenosyltransferase II (MATII), which methylates the DNA and histone and epigenetically represses gene expression [25][26]. Recent studies also implicate the interaction of Bach1 with proteins other than small MAF proteins in occupying DNA motifs dissimilar to MARE-like sequences and exhibiting MAFK-independent DNA binding [27]. Therefore, it is highly probable that the Bach1 deletion may activate Nrf2/MAFK-independent targeted genes. Indeed, the functional genomics analysis has revealed 1154 differentially expressed genes in the VMB region between the wild-type and Bach1 knockout mice. By using the motif analysis of previously published Bach1 ChIP-seq data and the microarray data, researchers have identified both ARE and non-ARE gene expression profiles [28]. Surprisingly, 52% of 2242 Bach1-associated genes have non-ARE motifs. Pathway enrichment analyses (Metascape) [29] demonstrate that ARE-associated genes are enriched for pathways involved in oxygen sensing/regulation and neuronal death. In contrast, non-ARE-bound genes primarily affect DNA binding, inflammatory response, apoptosis, and neuronal death. Recently, the CRISPR/Cas9 mediated Bach1 knockout in a pancreatic cancer cell line (AsPC1) shows novel Bach1 targeted genes such as CLDN3, CLDN4, PKP2, CHD1, and FOXA1, a subset of genes that enhance the metastasis of tumor cells [30]. Interestingly, most Bach1 target genes contain ARE-like motifs in the Bach1 binding regions. However, gene expression of others involved additional mechanisms besides Bach1. For example, threse authoarchers observed that CDH1 expression was indirectly regulated by Bach1. It is thought that Bach1 inhibits the expression of CDH1 by repressing FOXOA1 and activating SNAI2, the repressor and activator genes of CDH1, respectively. However, the double knockdown of Bach1 and FOXOA1 did not change CDH1 expression. These findings suggest that the transcriptional regulation of Bach1 is not only a direct effect but also a secondary mechanism involving additional transcription factors that likely play a role in gene expression.
Recent advances in elucidating Bach1 function have demonstrated that it also exhibits transcription-independent roles. A series of reports from Li et al. [13][31][32] has shed light on the transcription-independent role of Bach1 in facilitating chromosomal alignment during mitosis. Mitosis-specific phosphorylation of Bach1 at various sites switches its primary function from transcription to mitosis, which, along with HMMR and CRM1, stabilizes the orientation of the mitotic spindle [32]. Together, these findings suggest that Bach1 is a relatively new protein that holds enormous promise for future investigations into its role in normal physiology and pathophysiological conditions.

3. Role of Bach1 as a Mediator of Cellular Redox Homeostasis

Recent evidence has suggested that Bach1 plays a vital role in maintaining cellular redox homeostasis. Investigative studies involving the knockdown and knockout of Bach1 have demonstrated that these manipulations significantly increase the expression of HO-1, an Nrf2 target gene. It has been shown that Nrf2 cannot bind to the ARE site at the promoter region of the HO-1 gene in the presence of Bach1, suggesting the crucial role of Bach1 in repressing the HO-1 expression [33]. HO-1 is a rate-limiting enzyme involved in heme catabolism. Degradation of heme yields iron, carbon monoxide, and biliverdin, which is transformed into bilirubin under the catalytic effect of biliverdin reductase. Heme degradation products are all biologically active molecules mainly implicated in tissue redox homeostasis to mitigate OS and counteract its adverse effects [34][35]. HO-1 is pivotal in regulating redox homeostasis because of its anti-inflammatory, antioxidant, and anti-apoptotic properties. Besides its role as a rate-limiting enzyme in heme catabolism, HO-1 has several non-canonical functions, including chaperone activity mediated by protein–protein interactions, transcriptional regulation, intracellular compartmentalization, mitochondrial bioenergetics, and immunomodulation [36][37]. Furthermore, considerable evidence proves that HO-1 induction renders therapeutic effects in animal models of various disorders [reviewed in [35]].
Bach1 possesses four critical cysteine-proline (CP) motifs at its C-terminal that are instrumental in heme binding [38][39]. Therefore, one significant role of Bach1 is to maintain free heme levels in the cytoplasm by regulating the expression of various genes involved in hemoglobin synthesis [40], iron metabolism [25][26], and heme elimination [39]. On the same grounds, due to several cysteine residues in its integral protein structure, Bach1 responds to alterations in the cellular redox states. Accordingly, it acts as a cellular redox regulator [41]. Additionally, similar to other cellular redox sensors, well-known sulfhydryl oxidizing agents such as diamide [41] and other electrophiles, including cobalt protoporphyrin [42], cadmium [16], and HNE, modulate Bach1 activity [41]. Furthermore, Kitamuro et al. demonstrate the hypoxia-induced repression of HO-1 induction in three human cell lines by modulating Bach1 expression [43]. Hence, this evidence strongly implicates Bach1 in modulating cellular redox potential and maintaining cellular homeostasis.
Indeed, the approach of modulating Bach1 activity to attenuate OS response has been successfully used in various preclinical models of OS-mediated disorders. Notably, Bach1-deficient mice show an anti-atherosclerotic effect in high-fat diet-fed apolipoprotein E (Apo E) knockout mice, which are highly susceptible to the deposition of atherosclerotic plaques in the blood vessels. The suppression of atherosclerotic plaque in Bach1-deficient mice is abolished by tin protoporphyrin (SnPP), an HO-1 inhibitor, implicating HO-1 dependency in the protective phenotype [44]. The same group also demonstrates the suppression of neointimal formation after cuff injury in Bach1-deficient mice, which was mediated by the reduced proliferation of vascular smooth muscle cells (SMC) and increased phagocytic activity compared to wild-type mice [45]. Furthermore, Mito et al. show the cardioprotective effect of Bach1 ablation in an in vivo model where transverse aortic constriction results in left ventricular (LV) hypertrophy and remodeling, ultimately leading to heart failure. Bach1 gene deletion prevented LV hypertrophy, fibrosis, and wall thickening and maintained the left ventricle’s contractile function [46].
Similarly, the Bach1 gene deletion has shown antioxidant, anti-apoptotic, and anti-inflammatory effects against the indomethacin-induced intestinal injury model [47][48] and the lipopolysaccharide (LPS) and D-galactosamine (GalN) induced hepatotoxicity [49]. Bach1 knockout mice are protected against 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in which isolated peritoneal macrophages have characteristics of the M2 state (a state involved in immunosuppression and tissue repair) and exhibited a high level of HO-1 expression [50]. An investigation into the effect of Bach1 ablation on osteoarthritis reveals significant protection against age-associated and surgically induced osteoarthritis [51]. Interestingly, the same study shows that the increased HO-1 expression because of Bach1-ablation and the subsequent antioxidant effects are crucial in imparting a protective effect against osteoarthritis [51]. Furthermore, RANKL is shown to induce the nuclear translocation of Bach1, which neutralizes the Nrf2-driven cellular antioxidant capability and mediates the osteoclastogenic effect of RANKL. Thus, in an in vivo model of bone destruction, nuclear export of Bach1 by increasing heme levels following administration of 5-aminolevulinic acid (ALA) and ferrous citrate exhibits a protective effect [52]. The same group showed that pharmacological Bach1 inhibition effectuated RANKL-mediated intracellular ROS and subsequently attenuated the RANKL-mediated bone resorption [53]. Thus, Bach1 ablation has beneficial effects against cardiovascular dysfunction, hepatotoxicity, intestinal toxicity, and osteoarthritis via the modulation of redox homeostasis.

4. Role of Bach1 as an Immunomodulator

Innate and acquired immunity plays a crucial role in maintaining an organism’s normal state of homeostasis. The resulting inflammatory response is a natural process in repairing tissues and the organism’s defense against infections and harmful agents. However, the chronic ectopic stimulation of immune pathways can lead to auto-inflammatory damage to the cellular system, eventually resulting in several disorders. The transcription factor Nrf2 has been demonstrated to inhibit the maturation of dendritic cells (DCs) in vitro and modulate immune responses [54]. Indeed, a well-known Nrf2 activator, dimethyl fumarate (DMF), exerts neuroprotective and anti-inflammatory effects against multiple sclerosis (MS), an autoimmune-related disorder [55][56], and is currently being clinically employed in treating MS [56]. Being a member of the same family of transcription factors as Nrf2 and as Nrf2’s competitive repressor of ARE sites, Bach1 is expected to play an essential role in innate and acquired immunity. Recent studies have established the crucial role of Bach1 in hematopoiesis [57][58][59], and it is thus speculated to be a critical regulator of the immune system. A recent investigation depicts the role of Bach1 in regulating steady-state myelopoiesis, normal immune function, and the development of autoimmune disorders [60]. The study results showed that Bach1 gene deletion does not cause any changes in the percentage of T cells, B cells, natural killer cells, and erythrocytes. However, the population of macrophages and DCs is significantly reduced compared to controls. Moreover, Bach1 ablation results in partial protection in the murine experimental autoimmune encephalomyelitis (EAE) model of MS, which was shown to be mediated via a defective T-cell response due to the impaired development of antigen-presenting cells (APCs) such as macrophages and DCs [60]. This effect of Bach1 gene deletion depends on HO-1 induction. More recently, conditional deletion of Bach1 in endothelial cells attenuated atherosclerosis by reducing endothelial inflammation [61]. In human and mouse atherosclerotic plaques, Bach1 was upregulated in the endothelial cells. Endothelial Bach1 gene deletion decreased atherosclerotic lesions, macrophage content in plaques, expression of endothelial adhesion molecules ICAM-1, VCAM-1, and reduced plasma TNF-α and IL-1β levels in atherosclerotic mice.
Bach1 and Bach2 are known to affect B-cell development, as Bach1 and Bach2 are a part of the gene-regulatory network that finetunes the balance between innate immunity and acquired immunity [59]. The most notable immune response-linked genes targeted by Bach1 include HO-1, IL-6, and MCP-1, all of which have well-known immunomodulatory effects [62][63]. A few studies have reported robust expression of Bach1 in neonatal lung tissue. Bach1 ablation is found to be protective against hyperoxic lung injury in newborn mice [63][64]. The underlying protective mechanism involved Bach1-inhibition mediated upregulation of HO-1 and IL-6 expression concomitant with the transient overexpression of proinflammatory cytokine MCP-1 [62]. Besides, a deficiency in Bach1 ameliorates 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis by modulating the development of macrophages and APCs [50]. The study shows that Bach1 deficiency promotes the M2-type macrophages, which induce an extensive anti-inflammatory response upon injection into the TNBS-treated wild-type mice, as demonstrated by the reduced expression of pro-inflammatory markers such as TNF-α, IFN-γ, and KC in the colon [50]. Bach1 plays a regulatory role in the pathophysiology of lupus nephritis (LN), particularly in determining the pro-inflammatory or anti-inflammatory phenotype of M2 macrophages by modulating the HO-1 expression [65]. Recently, Pradhan et al. demonstrated that bone-marrow-derived macrophages show reduced mitochondrial oxidative phosphorylation and increased glycolysis resulting in the activation of the NLRP3 inflammasome [66]. Isolated bone-marrow-derived macrophages from Bach1 knockout mice showed enhanced mitochondrial membrane potential and generation of mitochondrial ROS along with reduced levels of mitophagy compared to wild-type, despite significant upregulation of HO-1 in the Bach1 knockout bone-marrow-derived macrophages. These findings suggest that Bach1 is a regulator of cellular bioenergetics with functional consequences for immunomodulatory activities characterized by the coexistence of both pro-inflammatory inflammasome activation and anti-inflammatory effects due to high levels of HO-1 due to Bach1 deficiency in macrophage activation. While mitochondrial dysfunction and NLRP3 activation were observed in isolated bone-marrow-derived macrophages from Bach1 knockout mice in culture, it is unknown whether such a mechanism exists in vivo in other cell types or tissues from the Bach1 knockout mice. Furthermore, the significance of these findings in modulating tissue inflammation, mitochondrial dysfunction, and cellular pathology in Bach1 knockout mice is currently unclear. A recent study by Cai et al. demonstrated that systemic and tissue inflammation was attenuated in Bach1 knockout mice along with improved organ function and survival following polymicrobial sepsis induced by cecal ligation and puncture (CLP). Besides attenuating tissue inflammation, the absence of Bach1 reduced mitochondrial dysfunction after CLP-sepsis by preserving bioenergetics function in mitochondria isolated from the liver of CLP-sepsis-induced mice. Gene expression profiling by RNA-seq analysis in the liver of Bach1 knockout mice compared to wild-type mice subjected to CLP-sepsis showed that the most significantly affected genes were predominantly associated with lipid metabolism, oxidoreductase activity, and significant upregulation in HO-1 expression. Although Bach1 ablation after CLP-sepsis preserved mitochondrial bioenergetics, the RNA-seq analysis failed to observe the upregulation of genes that encode proteins modulate mitochondrial bioenergetics in the Bach1 knockout mice. However, the inhibition of HO-1 activity by Zn protoporphyrin-9 worsened organ function in Bach1 knockout mice following CLP, suggesting a crucial role of HO-1 in these protective phenotypes in Bach1 knockout mice [67]. Many studies show the anti-inflammatory effects of Bach1 ablation in different OS-related disorders such as steatohepatitis and drug-induced hepatic and intestinal toxicity [47][68][69]. Hence, considering the existing knowledge stated above, it can be reasonably proposed that the Bach1/HO-1 axis plays a vital role in acquired and innate immunity. This also implies that the Bach1/HO-1 axis can be exploited as a drug target for auto-immune and metabolic disorders.

5. Bach1, a Modulator of Mitochondrial Bioenergetics and Iron Homeostasis

The Nrf2 pathway regulates the expression of various genes involved in maintaining the normal functionality of the mitochondrial bioenergetics [70]. Other investigators and researchers have elucidated the role of Nrf2 activation in regulating mitochondrial bioenergetics, metabolomics, and metabolic function, which has been previously discussed (reviewed in [70]). A subset of Bach1-targeted genes is mitochondrial-associated genes that modulate the diverse mitochondrial processes ranging from mitochondrial transcription and biogenesis to mitochondrial bioenergetics [71]. For instance, nuclear respiratory factor 1 (NRF1) is a transcriptional regulator of mitochondrial biogenesis, which has recently been shown to be targeted by Bach1 through secondary mechanisms, as NRF1 lacks Bach1 binding sites [71]. Additionally, an increasing number of studies implicate abnormally elevated Bach1 levels playing a central role in the cancer cell metastasis [30][72]. A previous study has demonstrated that Bach1 negatively regulates the expression of several mitochondrial electron transport chain-related genes with a concomitant increase in mitochondrial acidification and decreased mitochondrial respiration [73]. The same study identified six mitochondrial genes, ATP5D (also known as ATP5F1D), COX15, UQCRC1, ATP5J (also known as ATP5PF), SLC25A22, and TIMM8B, which Bach1 directly regulates as potential Bach1 target genes [73]. In another report, Weil et al. have identified genes associated with glycolytic pathways, such as Hexokinase-2 (HK-2) and Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH), which are under direct regulation by Bach1 [74]. These authors demonstrated that they could attenuate lung cancer metastasis by inhibiting the glycolytic pathways. These findings, combined with mitochondrial dysfunction in PD due to reduced mitochondrial respiration, dampened mitochondrial biogenesis, and elevated mitochondrial acidification, suggest a potential benefit of targeting Bach1 in attenuating neuronal damage associated with PD.
By repressing the HO-1 in various cell types, Bach1 modulates heme degradation and the recycling of iron, which is cytotoxic in its free form. A recent study on Bach1 ChIP-seq performed in human kidney cells (HEK293) has identified ferritin light chain (Ftl), ferritin heavy chain (Fth), and ferroportin as direct targets of the Bach1 repression [71]. These results are corroborated by those of Nishizawa et al., which demonstrated that Bach1 represses the transcription of a group of genes, including the glutamate-cysteine ligase modifier subunit (Gclm), solute carrier family seven-member 11 (Slc7a11), Fth1, Ftl1, and solute carrier family 40 member 1 (Slc40a1), all of which are involved in glutathione synthesis or cellular iron metabolism [26]. Additionally, Haldar et al. demonstrate that Bach1 represses Spi-C expression, a transcription factor known to regulate iron recycling in the macrophages [75]. Consequently, these findings indicate that Bach1 plays a vital role in maintaining iron homeostasis by controlling the various cellular steps involved in iron uptake, degradation, export, and reabsorption [26][76][77]. Thus, inhibiting Bach1 from modulating iron homeostasis may be beneficial in PD.

6. Does Bach1 Play a Role in PD?

As discussed above and reported in multiple studies within various pathologies, Bach1 plays a critical regulatory role in influencing the gene expression of several genes involved in redox regulation, mitochondrial biogenesis, and inflammation. The functional genomic analysis reveals that Bach1 represses several Nrf2-mediated ARE and Nrf2-independent non-ARE genes and is involved in PD pathogenesis [28].
The results also demonstrated that Bach1 is up-regulated in the SN of MPTP-treated mice and human postmortem PD brains. For the first time, these findings indicate that Bach1 up-regulation is associated with the demise of SNpc dopaminergic neurons of PD brains, as Bach1 knockout mice exhibited a significant reduction in MPTP-induced dopaminergic neuronal cell death in both acute and sub-acute models [28]. The attenuation of neuronal death in the SNpc is accompanied by the attenuated loss of dopamine and its metabolites in the striatum and reduced inflammation in the midbrain, as evidenced by the reduced expression of glial activation markers in Bach1 knockout mice compared to the MPTP-treated wild-type mice. Furthermore, gene expression analyses show that the ablation of Bach1 causes a significant up-regulation of 1164 genes in the VMB of mice. Bioinformatic analyses reveal that 33% of these differentially regulated genes harbor classic ARE motifs (TGA(G/C)TC) followed by the ETS motif. Genes associated with Bach1-ARE motifs are enriched for pathways critical for oxygen-sensing regulation and neuronal death. In contrast, genes enriched with non-ARE motifs were involved in DNA binding, inflammatory response, apoptosis, and neuronal death. Because the Maf family of transcription factors heterodimerizes with Bach1 and ETS transcription factors during differentiation and immune response [53][54][55][56], Bach1 could regulate non-ARE genes through ETS/MAF interactions. An important observation is that a significant percentage of the up-regulated genes in the Bach1 knockout mice do not contain an ARE motif in their promoter regions and, therefore, belong to the non-ARE class of genes. This signifies that Bach1 might directly regulate the transcription of other genes, which are not involved in the OS response but possibly in different neuroprotective pathways. Most non-ARE genes regulated by Bach1 are represented by transcription factors and proteins that modulate neuronal cell survival. Therefore, it can be surmised that the ablation of Bach1 augments the endogenous expression of several cytoprotective genes. This finding is supported by studies demonstrating that Bach1 negatively regulates the expression of critical mitochondrial proteins such as ATP5D, NDUFA9, COX15, COX18, SLC25A15, UQRC1, and ATP5G3 [73] and preserves mitochondrial function during injury via HO-1 dependent mechanisms [67]. These proteins are essential for oxidative phosphorylation and the electron transport chain functions, cumulatively increasing glucose utilization through mitochondrial metabolism. Without Bach1, these proteins are upregulated to improve mitochondrial health. The results suggest that Bach1 deficiency can upregulate both Nrf2 and non-Nrf2 genes, which may have additional benefits in PD. These results provide a strong rationale for further validating Bach1 as a therapeutic target in chronic and genetic PD models.
The study by Ahuja and co-workers [28] convincingly demonstrates that Bach1 ablation has a pronounced neuroprotective effect in MPTP-induced parkinsonism and that Bach1 inhibition could serve as a drug target to prevent PD pathology. This necessitates the development of therapeutics to inhibit the physiological repressor function of Bach1 from activating the expression of cytoprotective genes. Hemin is a known physiological inhibitor of Bach1 DNA-binding activity and inducer of its nuclear export and degradation [17][19][39]. However, hemin also imparts a cytotoxic effect as, in its structure, the iron atom is coordinated by porphyrin ring pyrroles, which behave as a catalyst for oxygen/hydrogen peroxide activation and lipid peroxidation. Metalloporphyrins with metals other than iron, such as zinc (Zn protoporphyrin) or tin (Sn protoporphyrin), do not have such a catalytic activity. They can be considered canonical inhibitors of Bach1, which bind to the CP motifs of Bach1. Unfortunately, this class of small molecules is known to inhibit HO-1 activity, minimizing their protective effect to severe adverse effects [78]. The search for HMOX1 activators that do not exhibit HMOX1 enzyme inhibition has been performed by vTv Therapeutics LLC and identified a series of substituted benzimidazole/benzothiazole hits providing almost a 100-fold increase in HMOX1 protein expression [79]. The structural formula of novel HMOX1 activators has been widened to benzoxazoles [80]. Out of the hit compounds identified by vTv Therapeutics LLC. a novel non-electrophilic small molecule, N-(2-(2-hydroxyethoxy)ethyl)-1-methyl-2-((6-(trifluoromethyl)benzo[d]thiazol-2-yl)amino)-1H-benzo[d]imidazole-5-carboxamide (HPPE), has been further validated by MARE-luciferase and Neh2-luciferase assays [28]. HPPE is even more potent than hemin (acting at a lower concentration) at inhibiting Bach1-mediated transcriptional repression of target genes. Further structural analysis coupled with bioinformatic tools points to HPPE’s direct interaction with the heme binding site of Bach1. However, the inhibition of Bach1-mediated gene repression and the induction of Nrf2-regulated ARE genes remains incomplete unless Bach1 is exported from the nucleus to the cytosol. Perhaps this is one of the reasons why, despite significant Nrf2 accumulation in the nucleus of the DA neurons of a PD brain, it is insufficient to activate compensatory neuroprotective genes due to the presence of Bach1-mediated repression [81].
There is an urgent unmet need for safe, potent, and blood-brain barrier-permeable compounds that activate the antioxidant and anti-inflammatory signaling cascade within the CNS. The activation of the Nrf2 signaling pathway via Nrf2 activators reduces neurodegeneration in preclinical PD models and, thus, represents a validated target for developing disease-modifying therapeutic interventions for PD. However, a significant limitation of these Nrf2 activators is their highly electrophilic nature, which regrettably renders them unusable in PD treatment. An alternate approach is to develop non-electrophilic Nrf2 activators that rely on destabilizing the Keap1-Nrf2 binding non-covalently. Unfortunately, these activators have low potency and exhibit poor blood-brain barrier permeability. Therefore, currently, all types of Nrf2 activators working via the Nrf2 stabilization mechanism are not ideal candidates for PD treatment. Moreover, Nrf2 stabilization and the subsequent activation induce the expression of Bach1, a transcriptional repressor of Nrf2, via a feedback mechanism. Therefore, without breaking this feedback loop, Nrf2 stabilization through the interruption of the Nrf2-Keap1 interaction is insufficient to combat neurodegeneration in PD. Bach1, the repressor of Nrf2, represents a novel target that intrinsically modulates the pathways common to the Nrf2 axis. Furthermore, the availability of non-electrophilic Bach1 inhibitors represents an excellent opportunity to investigate the therapeutic potential of targeting Bach1 in different preclinical PD models. Combining the Nrf2 stabilizer with the Bach1 inhibitor could be mutually beneficial [82]. Such a strategy will increase the background level of the Nrf2 protein and simultaneously relieve the inhibition from Bach1, which has the potential to lower the doses of both drugs and allow their continuous administration in the treatment of chronic diseases. The promising results with genetic and pharmacological approaches to inhibit Bach1 in PD mouse models warrants further investigation into the validation of Bach1 inhibition as an alternate strategy for developing safer and more effective therapeutic interventions for PD and other chronic neurodegenerative diseases.

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