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

Ahuja, M.; Kaidery, N.A.; Attucks, O.C.; McDade, E.; Hushpulian, D.M.; Gaisin, A.; Gaisina, I.; Ahn, Y.H.; Nikulin, S.; Poloznikov, A.; Gazaryan, I.; Yamamoto, M.; Matsumoto, M.; Igarashi, K.; Sharma, S.M.; Thomas, B.

Авторы: Ahuja Manuj, Kaidery Navneet Ammal, Attucks Otis C., McDade Erin, Hushpulian Dmitry M., Gaisin Arsen, Gaisina Irina, Ahn Young Hoon, Nikulin Sergey, Poloznikov Andrey, Gazaryan Irina, Yamamoto Masayuki, Matsumoto Mitsuyo, Igarashi Kazuhiko, Sharma Sudarshana M., Thomas Bobby
Журнал: Proceedings of the National Academy of Sciences of the United States of America
Том: 118
Номер: 45
Год издания: 2021
Издательство: National Academy of Sciences
Местоположение издательства: United States
Номер статьи: e2111643118
DOI: 10.1073/pnas.2111643118
Аннотация: 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.
Добавил в систему: Газарян Ирина Георгиевна

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

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