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

  • Proc Natl Acad Sci U S A. 2021 Nov 9;118(45):e2111643118. doi: 10.1073/pnas.2111643118.
Manuj Ahuja  1  2 ,  Navneet Ammal Kaidery  1  2 ,  Otis C Attucks  3 ,  Erin McDade  3 ,  Dmitry M Hushpulian  4 ,  Arsen Gaisin  5 ,  Irina Gaisina  6 ,  Young Hoon Ahn  7 ,  Sergey Nikulin  4 ,  Andrey Poloznikov  4 ,  Irina Gazaryan  4  8  9 ,  Masayuki Yamamoto  10  11 ,  Mitsuyo Matsumoto  12 ,  Kazuhiko Igarashi  12 ,  Sudarshana M Sharma  13 ,  Bobby Thomas  14  2  15  16
Affiliations
  • 1. Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425.
  • 2. Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425.
  • 3. vTv Therapeutics LLC, High Point, NC 27265.
  • 4. Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow 109028, Russia.
  • 5. Integrated Molecular Structure Education and Research Center, Northwestern University, IL 60208.
  • 6. Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, IL 60612.
  • 7. Department of Chemistry, Wayne State University, Detroit, MI 48202.
  • 8. Department of Chemical Enzymology, M. V. Lomonosov Moscow State University, Moscow 119991, Russia.
  • 9. Department of Chemistry and Physical Sciences, Pace University, Pleasantville, NY 10570.
  • 10. Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
  • 11. Tohoku Medical Megabank Organization, Tohoku University Graduate School of Medicine, Sendai 980-8573, Japan.
  • 12. Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
  • 13. Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
  • 14. Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425; [email protected].
  • 15. Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425.
  • 16. Department of Drug Discovery, Medical University of South Carolina, Charleston, SC 29425.
PMID: 34737234 DOI: 10.1073/pnas.2111643118
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.

Keywords
Bach1; MPTP; Nrf2; Parkinson’s disease; transcriptional repressor.
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