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Bach1 derepression is neuroprotective in a mouse model of Parkinson's disease.
Ahuja, Manuj; Ammal Kaidery, Navneet; 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.
Afiliación
  • Ahuja M; Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425.
  • Ammal Kaidery N; Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425.
  • Attucks OC; Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425.
  • McDade E; Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425.
  • Hushpulian DM; vTv Therapeutics LLC, High Point, NC 27265.
  • Gaisin A; vTv Therapeutics LLC, High Point, NC 27265.
  • Gaisina I; Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow 109028, Russia.
  • Ahn YH; Integrated Molecular Structure Education and Research Center, Northwestern University, IL 60208.
  • Nikulin S; Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, IL 60612.
  • Poloznikov A; Department of Chemistry, Wayne State University, Detroit, MI 48202.
  • Gazaryan I; Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow 109028, Russia.
  • Yamamoto M; Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow 109028, Russia.
  • Matsumoto M; Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow 109028, Russia.
  • Igarashi K; Department of Chemical Enzymology, M. V. Lomonosov Moscow State University, Moscow 119991, Russia.
  • Sharma SM; Department of Chemistry and Physical Sciences, Pace University, Pleasantville, NY 10570.
  • Thomas B; Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Proc Natl Acad Sci U S A ; 118(45)2021 11 09.
Article en En | MEDLINE | ID: mdl-34737234
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Parkinson / Factores de Transcripción con Cremalleras de Leucina de Carácter Básico / Neuroprotección Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Aged / Aged80 / Animals / Female / Humans / Male Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Parkinson / Factores de Transcripción con Cremalleras de Leucina de Carácter Básico / Neuroprotección Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Aged / Aged80 / Animals / Female / Humans / Male Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos