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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Aged
  • Aged, 80 and over
  • Animals
  • Antioxidant Response Elements
  • Basic-Leucine Zipper Transcription Factors / antagonists & inhibitors
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Case-Control Studies
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Neuroprotection*
  • Parkinson Disease / metabolism
  • Parkinson Disease / therapy*
  • Rats

Substances

  • BACH1 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine