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May 18, 2026
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Bach1 derepression is neuroprotective in a mouse model of Parkinson’s disease

Proceedings of the National Academy of Sciences of the United States of America. 2021. Vol. 118. No. 45. Article e2111643118.
Ahuja M., Ammal Kaidery N., Attucks O., McDade E., Hushpulian D., Gaisin A., Gaisina I., Ahn Y. H., Nikulin S., Poloznikov A., Gazaryan I. G., Yamamoto M., Matsumoto M., Igarashi K., Sharma S., Thomas B.

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 .

Research target: Basic Medicine Biology
Language: English
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Keywords: болезнь ПаркинсонаParkinson’s diseaseMPTPNrf2BACH1Nrf2BACH1transcriptional repressorMPTPрепрессор транскрипции
Publication based on the results of:
Creation of a metastasis-on-chip microphysiological platform for studying the biology of the tumor process (mathematical modeling) (2021)
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