2. Academic Validation
  3. Bach1 derepression is neuroprotective in a mouse model of Parkinson's disease

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

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; thomasbo@musc.edu.
  • 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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