Researchers have found that the suppression of Bach1 protein, a known transcriptional repressor of the Nrf2 pathway, slows the deterioration of neurons in Parkinson’s diseased brains.
Parkinson’s disease (PD) is the one of the most frequently diagnosed neurodegenerative conditions, affecting over 10 million individuals globally and over a million people in the United States. While there is no cure for Parkinson’s disease, current treatments focus on treating motor symptoms rather than the underlying brain damage. Researchers from the Medical University of South Carolina (MUSC) have discovered a new role for the regulatory protein Bach1 in Parkinson’s disease.
Their findings, which were published in the Proceedings of the National Academy of Sciences on Oct. 25, indicated that levels of Bach1 were higher in postmortem PD-affected brains, and that cells lacking Bach1 were protected from the PD-related damage. They discovered a powerful Bach1 inhibitor, dubbed HPPE, in cooperation with vTv Therapeutics, that protected cells against inflammation and the development of harmful oxidative stress when given before or after the start of illness symptoms.
“This is the first evidence that Bach1 is dysregulated in Parkinson’s disease,” said Bobby Thomas, Ph.D., professor of Pediatrics in the College of Medicine and the SmartState COEE Endowed Chair in Pediatric Neurotherapeutics.
As the disease advances, brain cells that generate the chemical messenger dopamine begin to die, resulting in tremors and other motor dysfunction. Inflammation and the accumulation of harmful oxidative stress also cause damage to neurons as we age.
Many genes fight these damaging processes, and many of them are regulated by two proteins: Nrf2 and Bach1. Nrf2 activates the expression of approximately 250 genes involved in the cell’s defense against various stresses. Bach1, on the other hand, stops these genes from being active.
Thomas’ group discovered that Bach1 levels are higher in autopsied brains of PD patients as well as toxin-based preclinical PD models, indicating that elevated Bach1 levels may play a role in PD pathogenesis. To prove it, the researchers used a PD animal model to deplete Bach1 and found that dopamine-producing neurons were shielded from some of the damaging stress pathways.
The group studied the full genome of Bach1-depleted mice’s brains and looked at which genes were activated to see how the loss of Bach1 protected neurons against cumulative stress.
“What we found was that Bach1 not only represses the expression of protective genes that are under the control of Nrf2, but it also regulates the expression of many other genes not directly regulated by Nrf2,” said Thomas. “So there are additional advantages to inhibiting Bach1 besides just activating Nrf2. Ideally you would want a drug that inhibits Bach1 and also activates Nrf2.”
For this, Thomas teamed up with vTv Therapeutics of North Carolina to produce Bach1 inhibitors. vTv uncovered numerous possible candidates using its own TTP Translational Technology platform, which Thomas confirmed. In vitro tests showed that the leading candidate, HPPE, was a better Bach1 inhibitor. Importantly, HPPE was a strong Nrf2 activator.
As a result, HPPE-based pharmacological intervention has the dual effect of stabilizing Nrf2 while also suppressing Bach1. But, in a preclinical PD mouse model, how would HPPE work?
A neurotoxin-based PD mouse model was used to investigate the efficacy of HPPE. When administered before or after the beginning of illness symptoms, HPPE reduced the severity of toxin-induced PD symptoms. HPPE protects neurons against damaging pathways by turning on antioxidant genes and shutting down pro-inflammatory genes, according to further research.
HPPE was shown to be more effective in protecting neurons than current FDA-approved Nrf2 activators like Tecfidera (dimethyl fumarate). Current activators are electrophiles, meaning they attach to and change proteins indefinitely, potentially causing cellular toxicity or immune system activation, and they come with a slew of negative side effects.
“The most interesting aspect of the study is that the Bach1 inhibitor is a non-electrophile, so it doesn’t work like the FDA-approved Nrf2 activators,” said Thomas. “As a result of this difference, hopefully, HPPE will not demonstrate as many side effects.”
Disruption of Bach1 and the simultaneous activation of Nrf2 clearly provide a strong basis for using HPPE as a potential therapeutic in PD. But several questions remain unanswered. While there were no side effects observed with acute treatment using HPPE in the PD mouse model, one key goal moving forward is to determine what impacts, if any, long-term use of HPPE might have. Another key question centers on the benefits of modulating this pathway in more chronic models of PD, other cell types in the brain and potentially other dementias.
“This pathway may be beneficial whenever you have impairments in anti-inflammatory pathways or mitochondrial dysfunctions,” said Thomas. “I think any disease that has these kinds of etiologies would benefit from modulating this pathway.”
The study was published in PNAS, on November 9th, 2021.
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.
Manuj Ahuja, Navneet Ammal Kaidery, Otis C. Attucks, Erin McDade, Dmitry M. Hushpulian, Arsen Gaisin, Irina Gaisina, Young Hoon Ahn, Sergey Nikulin, Andrey Poloznikov, Irina Gazaryan, Masayuki Yamamoto, Mitsuyo Matsumoto, Kazuhiko Igarashi, Sudarshana M. Sharma, Bobby Thomas. Bach1 derepression is neuroprotective in a mouse model of Parkinson’s disease, Proceedings of the National Academy of Sciences Nov 2021, 118 (45) e2111643118; DOI: 10.1073/pnas.2111643118
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