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Bach1 derepression is neuroprotective in a mouse model of Parkinson’s disease
Journal article   Open access   Peer reviewed

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

Manuj Ahuja, Navneet Ammal Kaidery, Otis C. Attucks, Erin McDade, Dmitry M. Hushpulian, Arsen Gaisin, Irina Gaisina, Young Hoon Ahn, Sergey Nikulin, Andrey Poloznikov, …
Proceedings of the National Academy of Sciences - PNAS, v 118(45)
09 Nov 2021
DOI: https://doi.org/10.1073/pnas.2111643118
PMID: 34737234
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1073/pnas.2111643118View
Published, Version of Record (VoR) Open

Abstract

Significance The Keap1-Nrf2 signaling pathway is a promising therapeutic target for Parkinson’s disease (PD). Canonical Nrf2 activators targeting Keap1 thiols are known to be preventive but never effectively cure chronic neurodegeneration because of their electrophilic nature, resulting in nonspecific reactions with active cysteine residues in a variety of cellular proteins. We show that genetic and pharmacologic inhibition of the Nrf2 repressor Bach1 in a posttreatment regimen of experimental PD is neuroprotective by up-regulating Bach1-targeted pathways involving both Nrf2-dependent antioxidant response element (ARE) and non-ARE genes. Inhibition of Bach1 by a nonelectrophilic substituted benzimidazole is a promising therapeutic approach for PD. 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.

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Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Biochemistry & Molecular Biology
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